Isoquinolin-3-YL carboxamides and preparation and use thereof

ABSTRACT

Isoquinoline compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an isoquinoline compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, fibrotic disorders, bone or cartilage diseases, and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/130,842, filed Sep. 13, 2018, which is a continuation of U.S.application Ser. No. 15/499,013, filed Apr. 27, 2017, and claims thebenefit of U.S. Provisional Application No. 62/328,255, filed Apr. 27,2016, which are incorporated herein by reference in their entirety.

BACKGROUND Technical Field

This disclosure relates to inhibitors of one or more proteins in the Wntpathway, including inhibitors of one or more Wnt proteins, andcompositions comprising the same. More particularly, it concerns the useof an isoquinoline compound or salts or analogs thereof, in thetreatment of disorders characterized by the activation of Wnt pathwaysignaling (e.g., cancer, abnormal cellular proliferation, angiogenesis,fibrotic disorders, bone or cartilage diseases, and osteoarthritis), themodulation of cellular events mediated by Wnt pathway signaling, as wellas genetic diseases and neurological conditions/disorders/diseases dueto mutations or dysregulation of the Wnt pathway and/or of one or moreof Wnt signaling components. Also provided are methods for treatingWnt-related disease states.

Background

The Wnt growth factor family includes more than 10 genes identified inthe mouse and at least 19 genes identified in the human. Members of theWnt family of signaling molecules mediate many short- and long-rangepatterning processes during invertebrate and vertebrate development. TheWnt signaling pathway is known for its role in the inductiveinteractions that regulate growth and differentiation, and it also playsroles in the homeostatic maintenance of post-embryonic tissue integrity.Wnt stabilizes cytoplasmic 3-catenin, which stimulates the expression ofgenes including c-myc, c jun, fra-1, and cyclin D1. In addition,misregulation of Wnt signaling can cause developmental defects and isimplicated in the genesis of several human cancers. The Wnt pathway hasalso been implicated in the maintenance of stem or progenitor cells in agrowing list of adult tissues including skin, blood, gut, prostate,muscle, and the nervous system.

SUMMARY

The present disclosure provides methods and reagents, involvingcontacting a cell with an agent, such as an isoquinoline compound, in asufficient amount to antagonize a Wnt activity, e.g., to reverse orcontrol an aberrant growth state or correct a genetic disorder due tomutations in Wnt signaling components.

Some embodiments disclosed herein include Wnt inhibitors containing anisoquinoline core. Other embodiments disclosed herein includepharmaceutical compositions and methods of treatment using thesecompounds.

One embodiment disclosed herein includes a compound having the structureof Formula I:

as well as prodrugs and pharmaceutically acceptable salts thereof.

In some embodiments of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R⁴⁵;

R⁶ is selected from the group consisting of -aryl substituted with 1-5R³⁶ and a 6-membered heteroaryl optionally substituted with 1-6 R³⁷;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁸ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)_(p) aryl optionally substituted with 1-10 R⁴⁶, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-12 R⁴³, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁵ is independently selected from the group consisting ofunsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, two adjacent R⁴⁵ taken together form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R⁴⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁷ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each X is selected from the group consisting of O, S, and NH; and

each p is independently 0 or 1.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted —(C₁₋₃alkyl);

R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring; so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of -aryl substituted with 1-5R³⁶ and a 6-membered heteroaryl optionally substituted with 1-6 R³⁷;

R⁷ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹ and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹⁵ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R¹⁸ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are taken together toform a heterocyclyl optionally substituted with 1-10 R⁴⁰;

R²¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R²² and R²³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R²² and R²³ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R²⁴, R²⁵, and R²⁶ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R²⁷, R²⁸, and R²⁹ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R²⁷ and R²⁸ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³⁰ and R³¹ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R³⁰ and R³¹ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³² and R³³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

R³⁴ and R³⁵ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R³⁴ and R³⁵ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R³⁸ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl), —CN,and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl), —CN,and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl), —CN,and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl), and—CN;

each R⁴² is independently selected from the group consisting ofunsubstituted —(C_(1-s) alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl),—(C₁₋₄ alkylene)_(p) aryl optionally substituted with 1-10 R⁴⁶, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-12 R⁴³, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C_(1-s) haloalkyl), —CN,and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently, optionallysubstituted with one or more substituents as defined anywhere herein;

each R⁴⁴ is selected from the group consisting of halide, unsubstituted—(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁷ is independently selected from the group consisting ofunsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each X is selected from the group consisting of O, S, and NH;

each Y is selected from the group consisting of O and S; and

each p is independently 0 or 1.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, amino, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted—(C₁₋₃ alkyl);

R³ is a 5-membered heteroaryl optionally substituted with 1-4 R⁴⁵;

R⁶ is selected from the group consisting of -phenyl substituted with 1-5R³⁶, —(C₁₋₃ alkylene)_(p) pyridinyl optionally substituted with 1-6 R³⁷,and a 6-10 membered heteroaryl optionally substituted with 1-6 R³⁷;wherein the carbonyl of Formula I is attached to an aromatic ring of theheteroaryl; wherein —(C₁₋₃ alkylene) is optionally substituted with oneor more substituents as defined anywhere herein;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and —(C₁₋₄alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and —(C₁₋₄alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

each R³⁸ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) aryl optionally substituted with1-10 R⁴⁶, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substituted with1-12 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substitutedwith 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN,—OH, —C(═O)R⁵¹, —N(R⁵⁰)₂, and —(C₁₋₄ alkylene)_(p) carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R⁴⁴ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁵ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein;

alternatively, two adjacent R⁴⁵ taken together form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R⁴⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁷ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁴⁸ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁴⁹ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁵⁰ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)N(R⁴⁸)₂; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;

each R⁵¹ is a heteroaryl optionally substituted with 1-6 R⁵²;

each R⁵² is a -heterocyclyl optionally substituted with 1-10 R⁴⁶;

each X is selected from the group consisting of O, S, and NR⁴⁸; and eachp is independently 0 or 1.

In another embodiment of Formula (I):

R¹, R², R⁴, and R⁵ are independently selected from the group consistingof H, halide, amino, unsubstituted —(C₁₋₃ haloalkyl), and unsubstituted—(C₁₋₃ alkyl);

R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹ (when present) is a bond, only one of R¹¹-R⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring; so that:

when the nitrogen atom to which R⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R¹⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R¹⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the nitrogen atom to which R²¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁵ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁶ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁷ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁷ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁸ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁸ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R²⁹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R²⁹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁰ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁰ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³¹ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³¹ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³² is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³² is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³³ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³³ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁴ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁴ is a single bondconnecting R³ to the isoquinoline ring;

when the carbon atom to which R³⁵ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R³⁵ is a single bondconnecting R³ to the isoquinoline ring;

R⁶ is selected from the group consisting of -phenyl substituted with 1-5R³⁶, —(C₁₋₃ alkylene)_(p) pyridinyl optionally substituted with 1-6 R³⁷,and a 6-10 membered heteroaryl optionally substituted with 1-6 R³⁷;wherein the carbonyl of Formula I is attached to an aromatic ring of theheteroaryl; wherein —(C₁₋₃ alkylene) is optionally substituted with oneor more substituents as defined anywhere herein;

R⁷ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting ofa single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R⁷ and R⁸, R⁸ and R⁹, or R⁹ and R¹⁰ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 R⁴⁰ and -carbocyclyloptionally substituted with 1-12 R⁴¹;

R¹⁵ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁶ and R¹⁷ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R¹⁸ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are taken together toform a heterocyclyl optionally substituted with 1-10 R⁴⁰;

R²¹ is selected from the group consisting of a single bond, H,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein;

R²² and R²³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R²² and R²³ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R²⁴, R²⁵, and R²⁶ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹;

R²⁷, R²⁸, and R²⁹ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R²⁷ and R²⁸ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³⁰ and R³¹ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R³⁰ and R³¹ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

R³² and R³³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

R³⁴ and R³⁵ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

alternatively, R³⁴ and R³⁵ are taken together to form a ring which isselected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 R⁴⁰ and -carbocyclyl optionally substituted with1-12 R⁴¹;

each R³⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and —(C₁₋₄alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

each R³⁷ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and —(C₁₋₄alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴; whereineach —(C₁₋₄ alkylene) is, independently, optionally substituted with oneor more substituents as defined anywhere herein;

each R³⁸ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R³⁹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴⁰ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein;

each R⁴¹ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) aryl optionally substituted with1-10 R⁴⁶, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substituted with1-12 R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionally substitutedwith 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein;

each R⁴³ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN,—OH, —C(═O)R⁵¹, —N(R⁵⁰)₂, and —(C₁₋₄ alkylene)_(p) carbocyclyloptionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein;

each R⁴⁴ is selected from the group consisting of halide, unsubstituted—(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl), unsubstituted —(C₂₋₅alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;

each R⁴⁷ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁴⁸ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁴⁹ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl);

each R⁵⁰ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)N(R⁴⁸)₂; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;

each R⁵¹ is a heteroaryl optionally substituted with 1-6 R⁵²;

each R⁵² is a -heterocyclyl optionally substituted with 1-10 R⁴⁶;

each X is selected from the group consisting of O, S, and NR⁴⁸;

each Y is selected from the group consisting of O and S; and

each p is independently 0 or 1.

Some embodiments include stereoisomers and pharmaceutically acceptablesalts of a compound of Formula (I). Some embodiments includepharmaceutically acceptable salts of a compound of Formula (I).

Some embodiments include pro-drugs of a compound of Formula (I).

Some embodiments of the present disclosure include pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier, diluent, or excipient.

Other embodiments disclosed herein include methods of inhibiting one ormore members of the Wnt pathway, including one or more Wnt proteins byadministering to a patient affected by a disorder or disease in whichaberrant Wnt signaling is implicated, such as cancer and other diseasesassociated with abnormal angiogenesis, cellular proliferation, cellcycling and mutations in Wnt signaling components, a compound accordingto Formula (I). Accordingly, the compounds and compositions providedherein can be used to treat cancer, to reduce or inhibit angiogenesis,to reduce or inhibit cellular proliferation and correct a geneticdisorder due to mutations in Wnt signaling components.

Non-limiting examples of diseases which can be treated with thecompounds and compositions provided herein include a variety of cancers,diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis,ankylosing spondylitis, psoriasis, scleroderma, mycotic and viralinfections, osteochondrodysplasia, Alzheimer's disease, lung disease,bone/osteoporotic (wrist, spine, shoulder and hip) fractures, articularcartilage (chondral) defects, degenerative disc disease (orintervertebral disc degeneration), polyposis coli,osteoporosis-pseudoglioma syndrome, familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia syndrome, Müllerian-duct regression and virilization,SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease, and Rett syndrome.

Some embodiments of the present disclosure include methods to preparecompounds of Formula (I).

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

Provided herein are compositions and methods for inhibiting one or moremembers of the Wnt pathway, including one or more Wnt proteins.

Some embodiments provided herein relate to a method for treating adisease or disorder including, but not limited to, cancers, diabeticretinopathy, pulmonary fibrosis, rheumatoid arthritis, sepsis,ankylosing spondylitis, psoriasis, scleroderma, mycotic and viralinfections, bone and cartilage diseases, Alzheimer's disease, lungdisease, osteoarthritis, bone/osteoporotic (wrist, spine, shoulder andhip) fractures, articular cartilage (chondral) defects, degenerativedisc disease (or intervertebral disc degeneration), polyposis coli, bonedensity and vascular defects in the eye (Osteoporosis-pseudogliomaSyndrome, OPPG), familial exudative vitreoretinopathy, retinalangiogenesis, early coronary disease, tetra-amelia, Müllerian-ductregression and virilization, SERKAL syndrome, type II diabetes, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

In some embodiments, non-limiting examples of bone and cartilagediseases which can be treated with the compounds and compositionsprovided herein include bone spur (osteophytes), craniosynostosis,fibrodysplasia ossificans progressiva, fibrous dysplasia, giant celltumor of bone, hip labral tear, meniscal tears, bone/osteoporotic(wrist, spine, shoulder and hip) fractures, articular cartilage(chondral) defects, degenerative disc disease (or intervertebral discdegeneration), osteochondritis dissecans, osteochondroma (bone tumor),osteopetrosis, relapsing polychondritis, and Salter-Harris fractures.

In some embodiments, pharmaceutical compositions are provided that areeffective for treatment of a disease of an animal, e.g., a mammal,caused by the pathological activation or mutations of the Wnt pathway.The composition includes a pharmaceutically acceptable carrier and acompound as described herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, “alkyl” means a branched, or straight chain chemicalgroup containing only carbon and hydrogen, such as methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl,n-pentyl, iso-pentyl, sec-pentyl and neo-pentyl. Alkyl groups can eitherbe unsubstituted or substituted with one or more substituents. In someembodiments, alkyl groups include 1 to 9 carbon atoms (for example, 1 to6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms).

As used herein, “alkenyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In variousembodiments, alkenyl groups can either be unsubstituted or substitutedwith one or more substituents. Typically, alkenyl groups will comprise 2to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2 to 4 carbonatoms, or 2 carbon atoms).

As used herein, “alkynyl” means a straight or branched chain chemicalgroup containing only carbon and hydrogen and containing at least onecarbon-carbon triple bond, such as ethynyl, 1-propynyl, 1-butynyl,2-butynyl, and the like. In various embodiments, alkynyl groups caneither be unsubstituted or substituted with one or more substituents.Typically, alkynyl groups will comprise 2 to 9 carbon atoms (forexample, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2 carbon atoms).

As used herein, “alkylene” means a bivalent branched, or straight chainchemical group containing only carbon and hydrogen, such as methylene,ethylene, n-propylene, iso-propylene, n-butylene, iso-butylene,sec-butylene, tert-butylene, n-pentylene, iso-pentylene, sec-pentyleneand neo-pentylene. Alkylene groups can either be unsubstituted orsubstituted with one or more substituents. Alkylene groups can besaturated or unsaturated (e.g., containing —C═C— or —C═C— subunits), atone or several positions. In some embodiments, alkylene groups include 1to 9 carbon atoms (for example, 1 to 6 carbon atoms, 1 to 4 carbonatoms, or 1 to 2 carbon atoms).

As used herein, “alkenylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon double bond, such as ethenylene,1-propenylene, 2-propenylene, 2-methyl-1-propenylene, 1-butenylene,2-butenylene, and the like. In various embodiments, alkenylene groupscan either be unsubstituted or substituted with one or moresubstituents. Typically, alkenylene groups will comprise 2 to 9 carbonatoms (for example, 2 to 6 carbon atoms, 2 to 4 carbon atoms, or 2carbon atoms).

As used herein, “alkynylene” means a bivalent branched, or straightchain chemical group containing only carbon and hydrogen and containingat least one carbon-carbon triple bond, such as ethynylene,1-propynylene, 1-butynylene, 2-butynylene, and the like. In variousembodiments, alkynylene groups can either be unsubstituted orsubstituted with one or more substituents. Typically, alkynylene groupswill comprise 2 to 9 carbon atoms (for example, 2 to 6 carbon atoms, 2to 4 carbon atoms, or 2 carbon atoms).

As used herein, “carbocyclyl” means a cyclic ring system containing onlycarbon atoms in the ring system backbone, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl. Carbocyclyls mayinclude multiple fused rings. Carbocyclyls may have any degree ofsaturation provided that at least one ring in the ring system is notaromatic. Carbocyclyl groups can either be unsubstituted or substitutedwith one or more substituents. In some embodiments, carbocyclyl groupsinclude 3 to 10 carbon atoms, for example, 3 to 6 carbon atoms.

As used herein, “aryl” means a mono-, bi-, tri- or polycyclic group withonly carbon atoms present in the ring backbone having 5 to 14 ringatoms, alternatively 5, 6, 9, or 10 ring atoms; and having 6, 10, or 14pi electrons shared in a cyclic array; wherein at least one ring in thesystem is aromatic. Aryl groups can either be unsubstituted orsubstituted with one or more substituents. Examples of aryl includephenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, andothers. In some embodiments, the aryl is phenyl.

As used herein, “arylalkylene” means an aryl-alkylene-group in which thearyl and alkylene moieties are as previously described. In someembodiments, arylalkylene groups contain a C₁₋₄alkylene moiety.Exemplary arylalkylene groups include benzyl and 2-phenethyl.

As used herein, the term “heteroaryl” means a mono-, bi-, tri- orpolycyclic group having 5 to 14 ring atoms, alternatively 5, 6, 9, or 10ring atoms; and having 6, 10, or 14 pi electrons shared in a cyclicarray; wherein at least one ring in the system is aromatic, and at leastone ring in the system contains one or more heteroatoms independentlyselected from the group consisting of N, O, and S. Heteroaryl groups caneither be unsubstituted or substituted with one or more substituents.Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl,oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl,isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl,benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl,pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, and others. In some embodiments, theheteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl,imidazolyl, pyranyl, pyrazinyl, and pyrimidinyl.

As used herein, “halo”, “halide” or “halogen” is a chloro, bromo,fluoro, or iodo atom radical. In some embodiments, a halo is a chloro,bromo or fluoro. For example, a halide can be fluoro.

As used herein, “haloalkyl” means a hydrocarbon substituent, which is alinear or branched, alkyl, alkenyl or alkynyl substituted with one ormore chloro, bromo, fluoro, and/or iodo atom(s). In some embodiments, ahaloalkyl is a fluoroalkyls, wherein one or more of the hydrogen atomshave been substituted by fluoro. In some embodiments, haloalkyls are of1 to about 3 carbons in length (e.g., 1 to about 2 carbons in length or1 carbon in length). The term “haloalkylene” means a diradical variantof haloalkyl, and such diradicals may act as spacers between radicals,other atoms, or between a ring and another functional group.

As used herein, “heterocyclyl” means a nonaromatic cyclic ring systemcomprising at least one heteroatom in the ring system backbone.Heterocyclyls may include multiple fused rings. Heterocyclyls may besubstituted or unsubstituted with one or more substituents. In someembodiments, heterocycles have 3-11 members. In six membered monocyclicheterocycles, the heteroatom(s) are selected from one to three of O, Nor S, and wherein when the heterocycle is five membered, it can have oneor two heteroatoms selected from O, N, or S. Examples of heterocyclylinclude azirinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl, pyranyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl, thiazinyl,thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl,piperidinyl, pyrazolidinyl imidazolidinyl, thiomorpholinyl, and others.In some embodiments, the heterocyclyl is selected from azetidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and tetrahydropyridinyl.

As used herein, “monocyclic heterocyclyl” means a single nonaromaticcyclic ring comprising at least one heteroatom in the ring systembackbone. Heterocyclyls may be substituted or unsubstituted with one ormore substituents. In some embodiments, heterocycles have 3-7 members.In six membered monocyclic heterocycles, the heteroatom(s) are selectedfrom one to three of O, N or S, and wherein when the heterocycle is fivemembered, it can have one or two heteroatoms selected from O, N, or S.Examples of heterocyclyls include azirinyl, aziridinyl, azetidinyl,oxetanyl, thietanyl, 1,4,2-dithiazolyl, dihydropyridinyl, 1,3-dioxanyl,1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, thiomorpholinyl, piperazinyl,pyranyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyridinyl, oxazinyl,thiazinyl, thiinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,isoxazolidinyl, piperidinyl, pyrazolidinyl imidazolidinyl,thiomorpholinyl, and others.

As used herein, “bicyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone. Bicyclic heterocyclyls may be substituted or unsubstitutedwith one or more substituents. In some embodiments, bicyclicheterocycles have 4-11 members with the heteroatom(s) being selectedfrom one to five of O, N or S. Examples of bicyclic heterocyclylsinclude 2-azabicyclo[1.1.0]butane, 2-azabicyclo [2.1.0]pentane,2-azabicyclo [1.1.1]pentane, 3-azabicyclo[3.1.0]hexane,5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane,octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane,7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane,7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, and the like.

As used herein, “spirocyclic heterocyclyl” means a nonaromatic bicyclicring system comprising at least one heteroatom in the ring systembackbone and with the rings connected through just one atom. Spirocyclicheterocyclyls may be substituted or unsubstituted with one or moresubstituents. In some embodiments, spirocyclic heterocycles have 5-11members with the heteroatom(s) being selected from one to five of O, Nor S. Examples of spirocyclic heterocyclyls include2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane,2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane,6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane,2,5-diazaspiro[3.6]decane, and the like.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more non-hydrogen atoms of the molecule. It will beunderstood that “substitution” or “substituted with” includes theimplicit proviso that such substitution is in accordance with permittedvalence of the substituted atom and the substituent, and that thesubstitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. Substituents can include, for example,—(C₁₋₉ alkyl) optionally substituted with one or more of hydroxyl, —NH₂,—NH(C₁₋₃ alkyl), and —N(C_-3 alkyl)₂; —(C₁₋₉ haloalkyl); a halide; ahydroxyl; a carbonyl [such as —C(O)OR, and —C(O)R]; a thiocarbonyl [suchas —C(S)OR, —C(O)SR, and —C(S)R]; —(C₁₋₉ alkoxyl) optionally substitutedwith one or more of halide, hydroxyl, —NH₂, —NH(C₁₋₃ alkyl), and —N(C₁₋₃alkyl)₂; —OPO(OH)₂; a phosphonate [such as —PO(OH)₂ and —PO(OR′)₂];—OPO(OR′)R″; —NRR′; —C(O)NRR′; —C(NR)NR′R″; —C(NR′)R″; a cyano; a nitro;an azido; —SH; —S—R; —OSO₂(OR); a sulfonate [such as —SO₂(OH) and—SO₂(OR)]; —SO₂NR′R″; and —SO₂R; in which each occurrence of R, R′ andR¹¹ are independently selected from H; —(C₁₋₉ alkyl); C₆₋₁₀ aryloptionally substituted with from 1-3R′″; 5-10 membered heteroaryl havingfrom 1-4 heteroatoms independently selected from N, O, and S andoptionally substituted with from 1-3 R′″; C₃₋₇ carbocyclyl optionallysubstituted with from 1-3 R′″; and 3-8 membered heterocyclyl having from1-4 heteroatoms independently selected from N, O, and S and optionallysubstituted with from 1-3 R′″; wherein each R′″ is independentlyselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxy), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl). In some embodiments, the substituent isselected from —(C₁₋₆ alkyl), —(C₁₋₆ haloalkyl), a halide (e.g., F), ahydroxyl, —C(O)OR, —C(O)R, —(C₁₋₆ alkoxyl), —NRR′, —C(O)NRR′, and acyano, in which each occurrence of R and R′ is independently selectedfrom H and —(C₁₋₆ alkyl).

As used herein, when two groups are indicated to be “linked” or “bonded”to form a “ring”, it is to be understood that a bond is formed betweenthe two groups and may involve replacement of a hydrogen atom on one orboth groups with the bond, thereby forming a carbocyclyl, heterocyclyl,aryl, or heteroaryl ring. The skilled artisan will recognize that suchrings can and are readily formed by routine chemical reactions. In someembodiments, such rings have from 3-7 members, for example, 5 or 6members.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically, theartisan recognizes that such structures are only a very small portion ofa sample of such compound(s). Such compounds are clearly contemplatedwithin the scope of this disclosure, though such resonance forms ortautomers are not represented herein.

The compounds provided herein may encompass various stereochemicalforms. The compounds also encompass diastereomers as well as opticalisomers, e.g., mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds. Separation ofthe individual isomers or selective synthesis of the individual isomersis accomplished by application of various methods which are well knownto practitioners in the art. Unless otherwise indicated, when adisclosed compound is named or depicted by a structure withoutspecifying the stereochemistry and has one or more chiral centers, it isunderstood to represent all possible stereoisomers of the compound.

The present disclosure includes all pharmaceutically acceptableisotopically labeled compounds of Formula I wherein one or more atomsare replaced by atoms having the same atomic number, but an atomic massor mass number different from the atomic mass or mass number whichpredominates in nature. Examples of isotopes suitable for inclusion inthe compounds of the disclosure include, but are not limited to,isotopes of hydrogen, such as ²H (deuterium) and ³H (tritium), carbon,such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F,iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen,such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as³⁵S.

The term “administration” or “administering” refers to a method ofproviding a dosage of a compound or pharmaceutical composition to avertebrate or invertebrate, including a mammal, a bird, a fish, or anamphibian, where the method is, e.g., orally, subcutaneously,intravenously, intralymphatic, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic device. Themethod of administration can vary depending on various factors, e.g.,the components of the pharmaceutical composition, the site of thedisease, the disease involved, and the severity of the disease.

A “diagnostic” as used herein is a compound, method, system, or devicethat assists in the identification or characterization of a health ordisease state. The diagnostic can be used in standard assays as is knownin the art.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes humans, cattle, horses, monkeys, dogs, cats, mice,rats, cows, sheep, pigs, goats, and non-human primates, but alsoincludes many other species.

The term “pharmaceutically acceptable carrier”, “pharmaceuticallyacceptable diluent” or “pharmaceutically acceptable excipient” includesany and all solvents, co-solvents, complexing agents, dispersion media,coatings, isotonic and absorption delaying agents and the like which arenot biologically or otherwise undesirable. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions. In addition, various adjuvants such as arecommonly used in the art may be included. These and other such compoundsare described in the literature, e.g., in the Merck Index, Merck &Company, Rahway, N.J. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 12th Ed., The McGraw-Hill Companies.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of the compounds providedherein and, which are not biologically or otherwise undesirable. In manycases, the compounds provided herein are capable of forming acid and/orbase salts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Many such salts are known in the art, forexample, as described in WO 87/05297. Pharmaceutically acceptable acidaddition salts can be formed with inorganic acids and organic acids.Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium, and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine.

“Patient” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate, or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate. In some embodiments, the patient is a human.

A “therapeutically effective amount” of a compound as provided herein isone which is sufficient to achieve the desired physiological effect andmay vary according to the nature and severity of the disease condition,and the potency of the compound. “Therapeutically effective amount” isalso intended to include one or more of the compounds of Formula I incombination with one or more other agents that are effective to treatthe diseases and/or conditions described herein. The combination ofcompounds can be a synergistic combination. Synergy, as described, forexample, by Chou and Talalay, Advances in Enzyme Regulation (1984), 22,27-55, occurs when the effect of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. It will be appreciated that different concentrations may beemployed for prophylaxis than for treatment of an active disease. Thisamount can further depend upon the patient's height, weight, sex, ageand medical history.

A therapeutic effect relieves, to some extent, one or more of thesymptoms of the disease.

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a compound or pharmaceutical composition as providedherein for therapeutic purposes. The term “therapeutic treatment” refersto administering treatment to a patient already suffering from a diseasethus causing a therapeutically beneficial effect, such as amelioratingexisting symptoms, ameliorating the underlying metabolic causes ofsymptoms, postponing or preventing the further development of adisorder, and/or reducing the severity of symptoms that will or areexpected to develop.

Compounds

The compounds and compositions described herein can be used asanti-proliferative agents, e.g., anti-cancer and anti-angiogenesisagents, and/or as inhibitors of the Wnt signaling pathway, e.g., fortreating diseases or disorders associated with aberrant Wnt signaling.In addition, the compounds can be used as inhibitors of one or morekinases, kinase receptors, or kinase complexes. Such compounds andcompositions are also useful for controlling cellular proliferation,differentiation, and/or apoptosis.

Some embodiments of the present disclosure include compounds of FormulaI:

or salts, pharmaceutically acceptable salts, or prodrugs thereof.

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H, halide, unsubstituted —(C₁₋₃ haloalkyl), andunsubstituted —(C₁₋₃ alkyl);

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H, halide, amino, unsubstituted —(C₁₋₃haloalkyl), and unsubstituted —(C₁₋₃ alkyl).

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and halide.

In some embodiments, R¹, R², R⁴, and R⁵ are independently selected fromthe group consisting of H and F.

In some embodiments, R¹, R², R⁴, and R⁵ are all H.

In some embodiments, R¹ is F, and R², R⁴, and R⁵ are all H.

In some embodiments, R² is F, and R¹, R⁴, and R⁵ are all H.

In some embodiments, R⁴ is F, and R¹, R², and R⁵ are all H.

In some embodiments, R⁵ is F, and R¹, R², and R⁴ are all H.

In some embodiments, R³ is a 5-membered heteroaryl ring optionallysubstituted as defined anywhere herein.

In some embodiments, R³ is 5-membered heteroaryl ring optionallysubstituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵;

In some embodiments, R³ is selected from the group consisting of:furanyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,thiophenyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,pyrrolyl optionally substituted with 1-4 (e.g., 1-3, 1-2, 1) R⁴⁵,

wherein each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, R³ is selected from the group consisting of:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹ (when present) is a bond, only one of R¹¹-R⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; for purposes ofclarification, any one of the nitrogen atoms attached to R⁷, R¹¹, R¹⁵,R¹⁸, or R²¹ can serve as the point of attachment of R³ to theisoquinoline ring; likewise, any one of the carbon atoms attached to R⁸,R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²², R²³, R²⁴, R²⁵, R²⁶,R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, or R³⁵ can serve as the point ofattachment of R³ to the isoquinoline ring.

In some embodiments, R⁶ is selected from the group consisting of -arylsubstituted with 1-5 (e.g., 1-4, 1-3, 1-2, 1) R³⁶ and a 6-memberedheteroaryl optionally substituted with 1-6 (e.g., 1-5, 1-4, 1-3, 1-2, 1)R³⁷.

In some embodiments, R⁶ is selected from the group consisting of -phenylsubstituted with 1-5 R³⁶, —(C₁₋₃ alkylene)_(p) pyridinyl optionallysubstituted with 1-6 R³⁷, and a 6-10 membered heteroaryl optionallysubstituted with 1-6 R³⁷; wherein the carbonyl of Formula I is attachedto an aromatic ring of the heteroaryl; wherein —(C₁₋₃ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein;

In some embodiments, R⁷ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R⁷ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R⁸, R⁹, and R⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R⁸, R⁹, and R⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, one of R⁷ and R⁸, R⁸ and R⁹, or R⁹ and R⁰ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7,1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴¹.

In some embodiments, R¹¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein-(C₁₋₄ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R¹¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹², R¹³, and R¹⁴ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ aretaken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 (e.g., 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴¹.

In some embodiments, R⁵¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein-(C₁_₄ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R¹⁵ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹⁶ and R¹⁷ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, one of R¹⁵ and R¹⁶ or R¹⁶ and R¹⁷ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7,1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴¹.

In some embodiments, R¹⁸ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein —(C₁₋₄ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R¹⁸ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R¹⁹ and R²⁰ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are takentogether to form a heterocyclyl optionally substituted with 1-10 (e.g.,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰.

In some embodiments, R²¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein-(C₁-4 alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, R²¹ is selected from the group consisting of asingle bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, R²² and R²³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²² and R²³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R²² and R²³ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R²⁴, R²⁵, and R²⁶ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²⁴, R²⁵, and R²⁶ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, one of R²⁴ and R²⁵ or R²⁵ and R²⁶ are takentogether to form a ring which is selected from the group consisting of-heterocyclyl optionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7,1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substitutedwith 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴¹.

In some embodiments, R²⁷, R²⁸, and R²⁹ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R²⁷, R²⁸, and R²⁹ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R²⁷ and R²⁸ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R³⁰ and R³¹ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³⁰ and R³¹ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R³⁰ and R³¹ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, R³² and R³³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³² and R³³ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R³⁸, and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are independently selected from thegroup consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, R³⁴ and R³⁵ are taken together to form a ring whichis selected from the group consisting of -heterocyclyl optionallysubstituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1)R⁴⁰ and -carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10,1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, each R³⁶ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —XR⁴², —C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R³⁶ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —XR⁴², —C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, each R³⁷ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —XR⁴², —C(O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyl optionallysubstituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R³⁷ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —XR⁴², —C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄alkylene)_(p) heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, each R³⁸ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 (e.g.,1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁴; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, each R³⁹ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 (e.g.,1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁴; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, each R⁴⁰ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 (e.g.,1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁴; wherein each—(C₁-4 alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, each R⁴¹ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN.

In some embodiments, each R⁴² is selected from the group consisting ofunsubstituted —(C_(1-s) alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl),), —(C₁₋₄alkylene)_(p) aryl optionally substituted with 1-10 (e.g., 1-9, 1-8,1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁶, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6,1-5, 1-4, 1-3, 1-2, 1) R⁴³, and —(C₁₋₄ alkylene)_(p) carbocyclyloptionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6,1-5, 1-4, 1-3, 1-2, 1) R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein.

In some embodiments, each R⁴² is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂_5 alkynyl), unsubstituted —(C₁₋₅haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) aryloptionally substituted with 1-10 R⁴⁶, —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-12 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, each R⁴³ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p) carbocyclyl optionally substituted with 1-12 (e.g.,1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴⁴; wherein each—(C₁₋₄ alkylene) is, independently, optionally substituted with one ormore substituents as defined anywhere herein.

In some embodiments, each R⁴³ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), —CN, —OH, —C(═O)R⁵¹, —N(R⁵⁰)₂, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein.

In some embodiments, each R⁴⁴ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN.

In some embodiments, each R⁴⁵ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁸, and-carbocyclyl optionally substituted with 1-12 (e.g., 1-11, 1-10, 1-9,1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R³⁹; wherein each —(C₁₋₄ alkylene)is, independently, optionally substituted with one or more substituentsas defined anywhere herein.

In some embodiments, each R⁴⁵ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p) heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein.

In some embodiments, two adjacent R⁴⁵ groups are taken together to forma ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 (e.g., 1-9, 1-8, 1-7, 1-6, 1-5, 1-4,1-3, 1-2, 1) R⁴⁰ and -carbocyclyl optionally substituted with 1-12(e.g., 1-11, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1-2, 1) R⁴¹.

In some embodiments, each R⁴⁶ is independently selected from the groupconsisting of halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), and —CN.

In some embodiments, each R⁴⁷ is independently selected from the groupconsisting of unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl).

In some embodiments, each R⁴⁷ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl).

In some embodiments, each R⁴⁸ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl).

In some embodiments, each R⁴⁹ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅haloalkyl).

In some embodiments, each R⁵⁰ is independently selected from the groupconsisting of H, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅alkenyl), unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅haloalkyl), and —(C₁₋₄ alkylene)N(R⁴⁸)₂; wherein —(C₁₋₄ alkylene) isoptionally substituted with one or more substituents as defined anywhereherein.

In some embodiments, each R⁵¹ is a heteroaryl optionally substitutedwith 1-6 R⁵².

In some embodiments, each R⁵² is a -heterocyclyl optionally substitutedwith 1-10 R⁴⁶.

In some embodiments, the heterocyclyl of —(C₁₋₄ alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R³⁸.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄ alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R³⁸.

In some embodiments, the heterocyclyl of —(C₁₋₄ alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R⁴³.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄ alkylene)_(p)heterocyclyl is optionally substituted with 1-10 R⁴³.

In some embodiments, the carbocyclyl of —(C₁₋₄ alkylene)_(p) carbocyclylis optionally substituted with 1-12 R⁴⁴.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴.

In some embodiments, the aryl of —(C₁₋₄ alkylene)_(p) aryl is optionallysubstituted with 1-10 R⁴⁶.

In some embodiments, the —(C₁₋₄ alkylene) of —(C₁₋₄ alkylene)_(p) arylis optionally substituted with 1-10 R⁴⁶.

In some embodiments, —(C₁₋₄ alkylene) is optionally substituted with 1-5halide or 1-5 unsubstituted —(C₁₋₃ alkyl).

In some embodiments, —(C₁₋₄ alkylene) is substituted with 1-2 fluorines.

In some embodiments, —(C₁₋₄ alkylene) is substituted with 1-2 methyls.

In some embodiments, each X is selected from the group consisting of O,S, and NH.

In some embodiments, each X is selected from the group consisting of O,S, and NR⁴⁸.

In some embodiments, each X is selected from the group consisting of Oand S.

In some embodiments, each X is selected from the group consisting of Oand NH.

In some embodiments, X is O.

In some embodiments, X is S.

In some embodiments, X is NH.

In some embodiments, X is NR⁴⁸.

In some embodiments, X is NMe.

In some embodiments, each Y is selected from the group consisting of Oand S.

In some embodiments, Y is O.

In some embodiments, Y is S.

In some embodiments, each m is independently 1 to 4 (e.g., 1-3, 1-2, 1).

In some embodiments, each n is independently 0 to 3 (e.g., 0-2, 0-1, 0).

In some embodiments, each p is independently 0 or 1.

In some embodiments, each q is independently 0 to 12 (e.g., 0-11, 0-10,0-9, 0-8, 0-7, 0-6, 0-5, 0-4, 0-3, 0-2, 0-1, 0).

In some embodiments, R³ is

In certain embodiments, R⁹ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R⁷ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R⁷ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R⁷ is selected from the group consisting of H andmethyl.

In some embodiments, R⁷ is methyl.

In some embodiments, R′ is —CD₃.

In some embodiments, R⁸ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), unsubstituted —(C₁₋₂ haloalkyl),and —(C₁₋₂ alkylene)OR⁴².

In some embodiments, R⁸ is selected from the group consisting of H, F,methyl, —CF₃, —(CH₂)OH, and —(CH₂)OMe.

In some embodiments, R⁸ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R⁸ is selected from the group consisting of H, F,and methyl.

In some embodiments, R⁸ is H.

In some embodiments, R¹⁰ is selected from the group consisting of H andhalide.

In some embodiments, R¹⁰ is selected from the group consisting of H andF.

In some embodiments, R¹⁰ is H.

In some embodiments, R³ is

In certain embodiments, R¹² is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R¹¹ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R¹¹ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R¹¹ is selected from the group consisting of H andmethyl.

In some embodiments, R¹¹ is methyl.

In some embodiments, R¹¹ is —CD₃.

In some embodiments, R¹³ is selected from the group consisting of H andhalide.

In some embodiments, R¹³ is selected from the group consisting of H andF.

In some embodiments, R¹⁴ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R¹⁴ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R¹⁴ is selected from the group consisting of H andmethyl.

In some embodiments, R¹¹ and R¹⁴ are both methyl.

In some embodiments, R³ is

In some embodiments, R³ is

and Y is S.

In some embodiments, R³ is

and Y is O.

In certain embodiments, R²⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R²⁸ is selected from the group consisting of H andhalide.

In some embodiments, R²⁸ is selected from the group consisting of H andF.

In some embodiments, R²⁹ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R²⁹ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R³ is

In some embodiments, R³ is

and X is S.

In some embodiments, R³ is

and X is O.

In certain embodiments, R³³ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In some embodiments, R³ is

In some embodiments, R³² is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), unsubstituted —(C₁₋₂ haloalkyl),and —N(R⁵³)₂.

In some embodiments, R³² is selected from the group consisting of H, F,methyl, —CF₃, —NHMe, and —NMe₂.

In some embodiments, R³² is selected from the group consisting of H andmethyl.

In some embodiments, R³² is methyl.

In some embodiments, R³ is

In certain embodiments, R²⁰ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R³ is

In certain embodiments, R¹⁶ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In certain embodiments, R¹⁷ is a single bond connecting R³ to theisoquinoline ring, i.e., R³ has the following formula:

In some embodiments, R¹⁵ is selected from the group consisting of H andunsubstituted —(C₁₋₂ alkyl).

In some embodiments, R¹⁵ is selected from the group consisting of H andmethyl.

In some embodiments, R¹⁵ is methyl.

In some embodiments, R¹⁵ is —CD₃.

In some embodiments, R³ is

and n is 1 to 3.

In some embodiments, R¹⁸ is selected from the group consisting of H,unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₂ haloalkyl), and —(C₃₋₄carbocyclyl) optionally substituted with 1-2 R³⁹.

In some embodiments, R¹⁸ is selected from the group consisting of H,methyl, —CF₃, and cyclopropyl optionally substituted with 1-2 R³⁹.

In some embodiments, R¹⁹ is selected from the group consisting of H,halide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R¹⁹ is selected from the group consisting of H, F,methyl, and —CF₃.

In some embodiments, R³⁹ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₃ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R³⁹ is selected from the group consisting of F,methyl, and —CF₃.

In some embodiments, R⁴⁰ is selected from the group consisting of H andunsubstituted —(C₁₋₂ alkyl).

In some embodiments, R⁴⁰ is selected from the group consisting of H andmethyl.

In some embodiments, R⁶ is selected from the group consisting of -arylsubstituted with 1-5 R³⁶ and a 6-membered heteroaryl optionallysubstituted with 1-6 R³⁷.

In some embodiments, R⁶ is selected from the group consisting of -phenylsubstituted with 1-5 R³⁶, and -pyridinyl optionally substituted with 1-4R³⁷.

In some embodiments, R⁶ is a -phenyl substituted with one R³⁶.

In some embodiments, R⁶ is a -pyridinyl substituted with one R³⁷.

In some embodiments, R⁶ is a -pyridin-2-yl substituted with one R³⁷.

In some embodiments, R⁶ is a -pyridin-3-yl substituted with one R³⁷.

In some embodiments, R⁶ is a -pyridin-4-yl substituted with one R³⁷.

In some embodiments, R³⁶ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₃ haloalkyl),—OR⁴², —NHR⁴², —C(O)N(C₁₋₃ alkyl)₂, —C(O)NH(C₁₋₃ alkyl), -heterocyclyloptionally substituted with 1-2 R⁴³, —(CH₂)heterocyclyl optionallysubstituted with 1-2 R⁴³, —(C₃₋₄ carbocyclyl) optionally substitutedwith 1-2 R⁴⁴, and —(CH₂)(C₃₋₄ carbocyclyl) optionally substituted with1-2 R⁴⁴.

In some embodiments, R³⁷ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₃ alkyl), unsubstituted —(C₁₋₃ haloalkyl),—OR⁴², —NHR⁴², —C(O)N(C₁₋₃ alkyl)₂, —C(O)NH(C₁_₃ alkyl), -heterocyclyloptionally substituted with 1-2 R⁴³, —(CH₂)heterocyclyl optionallysubstituted with 1-2 R⁴³, —(C₃₋₄ carbocyclyl) optionally substitutedwith 1-2 R⁴⁴, and —(CH₂)(C₃₋₄ carbocyclyl) optionally substituted with1-2 R⁴⁴.

In some embodiments, the heterocyclyl is selected from the groupconsisting of azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, morpholinyl, and tetrahydropyranyl.

In some embodiments, R⁴² is selected from the group consisting ofunsubstituted —(C₁₋₃ alkyl), and unsubstituted —(C₁₋₃ haloalkyl),—CH₂phenyl optionally substituted with 1-2 halides, -heterocyclyloptionally substituted with one —(C₁₋₃ alkyl), —CH₂ heterocyclyloptionally substituted with one —(C₁₋₃ alkyl), an unsubstituted-carbocyclyl, and an unsubstituted —CH₂ carbocyclyl.

In some embodiments, R⁴² is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, —CHF₂, —CF₃, and -heterocyclyloptionally substituted with one Me.

In some embodiments, R⁴² is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, —CHF₂, —CF₃,

In some embodiments, R⁴³ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₂ alkyl), unsubstituted —(C₁₋₂ haloalkyl),and -carbocyclyl optionally substituted with 1-2 halides.

In some embodiments, R⁴³ is selected from the group consisting of F,methyl, ethyl, —CF₃, and a cyclopropyl.

In some embodiments, R⁴⁴ is selected from the group consisting ofhalide, unsubstituted —(C₁₋₂ alkyl), and unsubstituted —(C₁₋₂haloalkyl).

In some embodiments, R⁴⁴ is selected from the group consisting of F,methyl, ethyl, —CF₃.

In some embodiments, R³⁶ is selected from the group consisting of F,methyl, ethyl, n-propyl, isopropyl, —O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³⁷ is selected from the group consisting of F,methy, ethyl, n-propyl, isopropyl, —O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³ is selected from the group consisting of:

wherein Y is S or O and R⁶ is a -aryl substituted with 1-5 R³⁶.

In some embodiments, R³ is selected from the group consisting of:

wherein Y is S or O and R⁶ is a 6-membered heteroaryl optionallysubstituted with 1-6 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -phenyl substituted with 1-5 R³⁶.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridinyl optionally substituted with 1-4 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -phenyl substituted with one R³⁶.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-2-yl substituted with one R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-3-yl substituted with one R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-4-yl substituted with one R³⁷.

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -phenyl substituted with one R³⁶; and R³⁶ is selected fromthe group consisting of F, methyl, ethyl, n-propyl, isopropyl, —O(C₁₋₃alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-2-yl substituted with one R³⁷; and R³⁷ is selectedfrom the group consisting of F, methyl, ethyl, n-propyl, isopropyl,—O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-3-yl substituted with one R³⁷; and R³⁷ is selectedfrom the group consisting of F, methyl, ethyl, n-propyl, isopropyl,—O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl)

In some embodiments, R³ is selected from the group consisting of:

and R⁶ is a -pyridin-4-yl substituted with one R³⁷; and R³⁷ is selectedfrom the group consisting of F, methyl, ethyl, n-propyl, isopropyl,—O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -phenyl substituted with one R³⁶; and R³⁶ is selected from thegroup consisting of F, methyl, —O(C₁₋₃ alkyl), —O(C₁₋₃ haloalkyl),

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -pyridin-2-yl substituted with one R³⁷; and R³⁷ is selected fromthe group consisting of

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -pyridin-3-yl substituted with one R³⁷; and R³⁷ is selected fromthe group consisting of

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -pyridin-4-yl substituted with one R³⁷; and R³⁷ is selected fromthe group consisting of

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -pyridin-3-yl substituted with one R³⁷; and R³⁷ is selected fromthe group consisting of

In some embodiments, R³ is selected from the group consisting of:

R⁶ is a -pyridin-4-yl substituted with one R³⁷; and R³⁷ is selected fromthe group consisting of

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of -phenyl optionallysubstituted with 1-2 R³⁶ and —(C₁₋₂ alkylene)_(p) pyridinyl optionallysubstituted with 1-2 R³⁷.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of -phenyl substituted with 1-2R³⁶ and -pyridinyl substituted with 1-2 R³⁷, and R³⁶ is selected fromthe group consisting of —XR⁴², —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-2 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-2 R⁴⁴, and R³⁷ is selectedfrom the group consisting of —XR⁴², —(C₁₋₄ alkylene)_(p) heterocyclyloptionally substituted with 1-2 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-2 R⁴⁴.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is selected from the group consisting of -phenyl substituted with 1R³⁶ and -pyridinyl substituted with 1 R³⁷, and R³⁶ is selected from thegroup consisting of -Xheterocyclyl optionally substituted with 1-2 R⁴³,-heterocyclyl optionally substituted with 1-2 R⁴³, and R³⁷ is selectedfrom the group consisting of -Xheterocyclyl optionally substituted with1-2 R⁴³, -heterocyclyl optionally substituted with 1-2 R⁴³.

In some embodiments, R³ is selected from the group consisting of:

R⁶ is -pyridinyl substituted with 1 R³⁷, and R³⁷ is selected from thegroup consisting of -Xheterocyclyl optionally substituted with 1-2 R⁴³,-heterocyclyl optionally substituted with 1-2 R⁴³, and X is selectedfrom the group consisting of O, S, —NH.

Illustrative compounds of Formula (I) are shown in Table 1.

TABLE 1

 1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

 24

 25

 26

 27

 28

 29

 30

 31

 32

 33

 34

 35

 36

 37

 38

 39

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52

 53

 54

 55

 56

 57

 58

 59

 60

 61

 62

 63

 64

 65

 66

 67

 68

 69

 70

 71

 72

 73

 74

 75

 76

 77

 78

 79

 80

 81

 82

 83

 84

 85

 86

 87

 88

 89

 90

 91

 92

 93

 94

 95

 96

 97

 98

 99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

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465Administration and Pharmaceutical Compositions

Some embodiments include pharmaceutical compositions comprising: (a) atherapeutically effective amount of a compound provided herein, or itscorresponding enantiomer, diastereoisomer or tautomer, orpharmaceutically acceptable salt; and (b) a pharmaceutically acceptablecarrier.

The compounds provided herein may also be useful in combination(administered together or sequentially) with other known agents.

Non-limiting examples of diseases which can be treated with acombination of a compound of Formula (I) and other known agents arecolorectal cancer, ovarian cancer, retinitis pigmentosa, maculardegeneration, diabetic retinopathy, idiopathic pulmonaryfibrosis/pulmonary fibrosis, and osteoarthritis.

In some embodiments, colorectal cancer can be treated with a combinationof a compound of Formula (I) and one or more of the following drugs:5-Fluorouracil (5-FU), which can be administered with the vitamin-likedrug leucovorin (also called folinic acid); capecitabine (XELODA®),irinotecan (CAMPOSTAR®), oxaliplatin (ELOXATIN®). Examples ofcombinations of these drugs which could be further combined with acompound of Formula (I) are FOLFOX (5-FU, leucovorin, and oxaliplatin),FOLFIRI (5-FU, leucovorin, and irinotecan), FOLFOXIRI (leucovorin, 5-FU,oxaliplatin, and irinotecan) and CapeOx (Capecitabine and oxaliplatin).For rectal cancer, chemo with 5-FU or capecitabine combined withradiation may be given before surgery (neoadjuvant treatment).

In some embodiments, ovarian cancer can be treated with a combination ofa compound of Formula (I) and one or more of the following drugs:Topotecan, Liposomal doxorubicin (DOXIL®), Gemcitabine (GEMZAR®),Cyclophosphamide (CYTOXAN®), Vinorelbine (NAVELBINE®), Ifosfamide(IFEX®), Etoposide (VP-16), Altretamine (HEXALEN®), Capecitabine(XELODA®), Irinotecan (CPT-11, CAMPTOSAR®), Melphalan, Pemetrexed(ALIMTA®) and Albumin bound paclitaxel (nab-paclitaxel, ABRAXANE®).Examples of combinations of these drugs which could be further combinedwith a compound of Formula (I) are TIP (paclitaxel [Taxol], ifosfamide,and cisplatin), VeIP (vinblastine, ifosfamide, and cisplatin) and VIP(etoposide [VP-16], ifosfamide, and cisplatin).

In some embodiments, a compound of Formula (I) can be used to treatcancer in combination with any of the following methods: (a) Hormonetherapy such as aromatase inhibitors, LHRH [luteinizinghormone-releasing hormone] analogs and inhibitors, and others; (b)Ablation or embolization procedures such as radiofrequency ablation(RFA), ethanol (alcohol) ablation, microwave thermotherapy andcryosurgery (cryotherapy); (c) Chemotherapy using alkylating agents suchas cisplatin and carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil and ifosfamide; (d) Chemotherapy usinganti-metabolites such as azathioprine and mercaptopurine; (e)Chemotherapy using plant alkaloids and terpenoids such as vincaalkaloids (i.e. Vincristine, Vinblastine, Vinorelbine and Vindesine) andtaxanes; (f) Chemotherapy using podophyllotoxin, etoposide, teniposideand docetaxel; (g) Chemotherapy using topoisomerase inhibitors such asirinotecan, topotecan, amsacrine, etoposide, etoposide phosphate, andteniposide; (h) Chemotherapy using cytotoxic antibiotics such asactinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin,idarubicin, epirubicin, bleomycin, plicamycin and mitomycin; (i)Chemotherapy using tyrosine-kinase inhibitors such as Imatinib mesylate(GLEEVEC®, also known as STI-571), Gefitinib (Iressa, also known asZD1839), Erlotinib (marketed as TARCEVA®), Bortezomib (VELCADE®),tamoxifen, tofacitinib, crizotinib, Bcl-2 inhibitors (e.g. obatoclax inclinical trials, ABT-263, and Gossypol), PARP inhibitors (e.g. Iniparib,Olaparib in clinical trials), PI3K inhibitors (e.g. perifosine in aphase III trial), VEGF Receptor 2 inhibitors (e.g. Apatinib), AN-152,(AEZS-108), Braf inhibitors (e.g. vemurafenib, dabrafenib and LGX818),MEK inhibitors (e.g. trametinib and MEK162), CDK inhibitors, (e.g.PD-0332991), salinomycin and Sorafenib; (j) Chemotherapy usingmonoclonal antibodies such as Rituximab (marketed as MABTHERA® orRITUXAN®), Trastuzumab (Herceptin also known as ErbB2), Cetuximab(marketed as ERBITUX®), and Bevacizumab (marketed as AVASTIN®); and (k)radiation therapy.

In some embodiments, diabetic retinopathy can be treated with acombination of a compound of Formula (I) and one or more of thefollowing natural supplements: Bilberry, Butcher's broom, Ginkgo, Grapeseed extract, and Pycnogenol (Pine bark).

In some embodiments, idiopathic pulmonary fibrosis/pulmonary fibrosiscan be treated with a combination of a compound of Formula (I) and oneor more of the following drugs: pirfenidone (pirfenidone was approvedfor use in 2011 in Europe under the brand name Esbriet®), prednisone,azathioprine, N-acetylcysteine, interferon-γ 1b, bosentan (bosentan iscurrently being studied in patients with IPF, [The American Journal ofRespiratory and Critical Care Medicine (2011), 184(1), 92-9]),Nintedanib (BIBF 1120 and Vargatef), QAX576 [British Journal ofPharmacology (2011), 163(1), 141-172], and anti-inflammatory agents suchas corticosteroids.

In some embodiments, a compound of Formula (I) can be used to treatidiopathic pulmonary fibrosis/pulmonary fibrosis in combination with anyof the following methods: oxygen therapy, pulmonary rehabilitation andsurgery.

In some embodiments, a compound of Formula (I) can be used to treatosteoarthritis in combination with any of the following methods: (a)Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen,naproxen, aspirin and acetaminophen; (b) physical therapy; (c)injections of corticosteroid medications; (d) injections of hyaluronicacid derivatives (e.g. Hyalgan, Synvisc); (e) narcotics, like codeine;(f) in combination with braces and/or shoe inserts or any device thatcan immobilize or support your joint to help you keep pressure off it(e.g., splints, braces, shoe inserts or other medical devices); (g)realigning bones (osteotomy); (h) joint replacement (arthroplasty); and(i) in combination with a chronic pain class.

In some embodiments, macular degeneration can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: Bevacizumab (Avastin®), Ranibizumab (Lucentis®),Pegaptanib (Macugen), Aflibercept (Eylea®), verteporfin (Visudyne®) incombination with photodynamic therapy (PDT) or with any of the followingmethods: (a) in combination with laser to destroy abnormal blood vessels(photocoagulation); and (b) in combination with increased vitamin intakeof antioxidant vitamins and zinc.

In some embodiments, retinitis pigmentosa can be treated with acombination of a compound of Formula (I) and one or more of thefollowing drugs: UF-021 (Ocuseva™), vitamin A palmitate and pikachurinor with any of the following methods: (a) with the Argus® II retinalimplant; and (b) with stem cell and/or gene therapy.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration, including, but not limited to, orally, subcutaneously,intravenously, intranasally, topically, transdermally,intraperitoneally, intramuscularly, intrapulmonarilly, vaginally,rectally, ontologically, neuro-otologically, intraocularly,subconjuctivally, via anterior eye chamber injection, intravitreally,intraperitoneally, intrathecally, intracystically, intrapleurally, viawound irrigation, intrabuccally, intra-abdominally, intra-articularly,intra-aurally, intrabronchially, intracapsularly, intrameningeally, viainhalation, via endotracheal or endobronchial instillation, via directinstillation into pulmonary cavities, intraspinally, intrasynovially,intrathoracically, via thoracostomy irrigation, epidurally,intratympanically, intracisternally, intravascularly,intraventricularly, intraosseously, via irrigation of infected bone, orvia application as part of any admixture with a prosthetic devices. Insome embodiments, the administration method includes oral or parenteraladministration.

Compounds provided herein intended for pharmaceutical use may beadministered as crystalline or amorphous products. Pharmaceuticallyacceptable compositions may include solid, semi-solid, liquid,solutions, colloidal, liposomes, emulsions, suspensions, complexes,coacervates and aerosols. Dosage forms, such as, e.g., tablets,capsules, powders, liquids, suspensions, suppositories, aerosols,implants, controlled release or the like. They may be obtained, forexample, as solid plugs, powders, or films by methods such asprecipitation, crystallization, milling, grinding, supercritical fluidprocessing, coacervation, complex coacervation, encapsulation,emulsification, complexation, freeze drying, spray drying, orevaporative drying. Microwave or radio frequency drying may be used forthis purpose. The compounds can also be administered in sustained orcontrolled release dosage forms, including depot injections, osmoticpumps, pills (tablets and or capsules), transdermal (includingelectrotransport) patches, implants and the like, for prolonged and/ortimed, pulsed administration at a predetermined rate.

The compounds can be administered either alone or in combination with aconventional pharmaceutical carrier, excipient or the like.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a compound as described herein in therange of 0.005% to 100% with the balance made up from non-toxic carriermay be prepared. The contemplated compositions may contain 0.001%-100%of a compound provided herein, in one embodiment 0.1-95%, in anotherembodiment 75-85%, in a further embodiment 20-80%. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a compound provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or morecompounds provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, etc. a compound provided herein andoptional pharmaceutical adjuvants in a carrier (e.g., water, saline,aqueous dextrose, glycerol, glycols, ethanol or the like) to form asolution, colloid, liposome, emulsion, complexes, coacervate orsuspension. If desired, the pharmaceutical composition can also containminor amounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, co-solvents, solubilizing agents, pH bufferingagents and the like (e.g., sodium acetate, sodium citrate, cyclodextrinderivatives, sorbitan monolaurate, triethanolamine acetate,triethanolamine oleate, and the like).

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 50 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.25 mg/Kg to about 20 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.50 mg/Kg to about 19 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 0.75 mg/Kg to about 18 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.0 mg/Kg to about 17 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.25 mg/Kg to about 16 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.50 mg/Kg to about 15 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 1.75 mg/Kg to about 14 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 2.0 mg/Kg to about 13 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 3.0 mg/Kg to about 12 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 4.0 mg/Kg to about 11 mg/Kg in humans.

In some embodiments, the unit dosage of compounds of Formula (I) isabout 5.0 mg/Kg to about 10 mg/Kg in humans.

In some embodiments, the compositions are provided in unit dosage formssuitable for single administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for twice a day administration.

In some embodiments, the compositions are provided in unit dosage formssuitable for three times a day administration.

Injectables can be prepared in conventional forms, either as liquidsolutions, colloid, liposomes, complexes, coacervate or suspensions, asemulsions, or in solid forms suitable for reconstitution in liquid priorto injection. The percentage of a compound provided herein contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thepatient. However, percentages of active ingredient of 0.01% to 10% insolution are employable, and could be higher if the composition is asolid or suspension, which could be subsequently diluted to the abovepercentages.

In some embodiments, the composition will comprise about 0.1-10% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-5% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.1-4% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.15-3% of theactive agent in solution.

In some embodiments, the composition will comprise about 0.2-2% of theactive agent in solution.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-96 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-72 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-48 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-24 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-12 hours.

In some embodiments, the compositions are provided in dosage formssuitable for continuous dosage by intravenous infusion over a period ofabout 1-6 hours.

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 300mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 5 mg/m² to about 100mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 10 mg/m² to about 50mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 50 mg/m² to about 200mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 75 mg/m² to about 175mg/m².

In some embodiments, these compositions can be administered byintravenous infusion to humans at doses of about 100 mg/m² to about 150mg/m².

It is to be noted that concentrations and dosage values may also varydepending on the specific compound and the severity of the condition tobe alleviated. It is to be further understood that for any particularpatient, specific dosage regimens should be adjusted over time accordingto the individual need and the professional judgment of the personadministering or supervising the administration of the compositions, andthat the concentration ranges set forth herein are exemplary only andare not intended to limit the scope or practice of the claimedcompositions.

In one embodiment, the compositions can be administered to therespiratory tract (including nasal and pulmonary) e.g., through anebulizer, metered-dose inhalers, atomizer, mister, aerosol, dry powderinhaler, insufflator, liquid instillation or other suitable device ortechnique.

In some embodiments, aerosols intended for delivery to the nasal mucosaare provided for inhalation through the nose. For optimal delivery tothe nasal cavities, inhaled particle sizes of about 5 to about 100microns are useful, with particle sizes of about 10 to about 60 micronsbeing preferred. For nasal delivery, a larger inhaled particle size maybe desired to maximize impaction on the nasal mucosa and to minimize orprevent pulmonary deposition of the administered formulation. In someembodiments, aerosols intended for delivery to the lung are provided forinhalation through the nose or the mouth. For delivery to the lung,inhaled aerodynamic particle sizes of about less than 10 μm are useful(e.g., about 1 to about 10 microns). Inhaled particles may be defined asliquid droplets containing dissolved drug, liquid droplets containingsuspended drug particles (in cases where the drug is insoluble in thesuspending medium), dry particles of pure drug substance, drug substanceincorporated with excipients, liposomes, emulsions, colloidal systems,coacervates, aggregates of drug nanoparticles, or dry particles of adiluent which contain embedded drug nanoparticles.

In some embodiments, compounds of Formula (I) disclosed herein intendedfor respiratory delivery (either systemic or local) can be administeredas aqueous formulations, as non-aqueous solutions or suspensions, assuspensions or solutions in halogenated hydrocarbon propellants with orwithout alcohol, as a colloidal system, as emulsions, coacervates, or asdry powders. Aqueous formulations may be aerosolized by liquidnebulizers employing either hydraulic or ultrasonic atomization or bymodified micropump systems (like the soft mist inhalers, the Aerodose®or the AERx® systems). Propellant-based systems may use suitablepressurized metered-dose inhalers (pMDIs). Dry powders may use drypowder inhaler devices (DPIs), which are capable of dispersing the drugsubstance effectively. A desired particle size and distribution may beobtained by choosing an appropriate device.

In some embodiments, the compositions of Formula (I) disclosed hereincan be administered to the ear by various methods. For example, a roundwindow catheter (e.g., U.S. Pat. Nos. 6,440,102 and 6,648,873) can beused.

Alternatively, formulations can be incorporated into a wick for usebetween the outer and middle ear (e.g., U.S. Pat. No. 6,120,484) orabsorbed to collagen sponge or other solid support (e.g., U.S. Pat. No.4,164,559).

If desired, formulations of the invention can be incorporated into a gelformulation (e.g., U.S. Pat. Nos. 4,474,752 and 6,911,211).

In some embodiments, compounds of Formula (I) disclosed herein intendedfor delivery to the ear can be administered via an implanted pump anddelivery system through a needle directly into the middle or inner ear(cochlea) or through a cochlear implant stylet electrode channel oralternative prepared drug delivery channel such as but not limited to aneedle through temporal bone into the cochlea.

Other options include delivery via a pump through a thin film coatedonto a multichannel electrode or electrode with a specially imbeddeddrug delivery channel (pathways) carved into the thin film for thispurpose. In other embodiments the acidic or basic solid compound ofFormula (I) can be delivered from the reservoir of an external orinternal implanted pumping system.

Formulations of the invention also can be administered to the ear byintratympanic injection into the middle ear, inner ear, or cochlea(e.g., U.S. Pat. No. 6,377,849 and Ser. No. 11/337,815).

Intratympanic injection of therapeutic agents is the technique ofinjecting a therapeutic agent behind the tympanic membrane into themiddle and/or inner ear. In one embodiment, the formulations describedherein are administered directly onto the round window membrane viatranstympanic injection. In another embodiment, the ion channelmodulating agent auris-acceptable formulations described herein areadministered onto the round window membrane via a non-transtympanicapproach to the inner ear. In additional embodiments, the formulationdescribed herein is administered onto the round window membrane via asurgical approach to the round window membrane comprising modificationof the crista fenestrae cochleae.

In some embodiments, the compounds of Formula (I) are formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG (like PEG ointments), and the like.

Suppositories for rectal administration of the drug (either as asolution, colloid, suspension or a complex) can be prepared by mixing acompound provided herein with a suitable non-irritating excipient thatis solid at ordinary temperatures but liquid at the rectal temperatureand will therefore melt or erode/dissolve in the rectum and release thecompound. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, poloxamers, mixtures of polyethyleneglycols of various molecular weights and fatty acid esters ofpolyethylene glycol. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter, is firstmelted.

Solid compositions can be provided in various different types of dosageforms, depending on the physicochemical properties of the compoundprovided herein, the desired dissolution rate, cost considerations, andother criteria. In one of the embodiments, the solid composition is asingle unit. This implies that one unit dose of the compound iscomprised in a single, physically shaped solid form or article. In otherwords, the solid composition is coherent, which is in contrast to amultiple unit dosage form, in which the units are incoherent.

Examples of single units which may be used as dosage forms for the solidcomposition include tablets, such as compressed tablets, film-likeunits, foil-like units, wafers, lyophilized matrix units, and the like.In one embodiment, the solid composition is a highly porous lyophilizedform. Such lyophilizates, sometimes also called wafers or lyophilizedtablets, are particularly useful for their rapid disintegration, whichalso enables the rapid dissolution of the compound.

On the other hand, for some applications the solid composition may alsobe formed as a multiple unit dosage form as defined above. Examples ofmultiple units are powders, granules, microparticles, pellets,mini-tablets, beads, lyophilized powders, and the like. In oneembodiment, the solid composition is a lyophilized powder. Such adispersed lyophilized system comprises a multitude of powder particles,and due to the lyophilization process used in the formation of thepowder, each particle has an irregular, porous microstructure throughwhich the powder is capable of absorbing water very rapidly, resultingin quick dissolution. Effervescent compositions are also contemplated toaid the quick dispersion and absorption of the compound.

Another type of multiparticulate system which is also capable ofachieving rapid drug dissolution is that of powders, granules, orpellets from water-soluble excipients which are coated with a compoundprovided herein so that the compound is located at the outer surface ofthe individual particles. In this type of system, the water-soluble lowmolecular weight excipient may be useful for preparing the cores of suchcoated particles, which can be subsequently coated with a coatingcomposition comprising the compound and, for example, one or moreadditional excipients, such as a binder, a pore former, a saccharide, asugar alcohol, a film-forming polymer, a plasticizer, or otherexcipients used in pharmaceutical coating compositions.

Also provided herein are kits. Typically, a kit includes one or morecompounds or compositions as described herein. In certain embodiments, akit can include one or more delivery systems, e.g., for delivering oradministering a compound as provided herein, and directions for use ofthe kit (e.g., instructions for treating a patient). In anotherembodiment, the kit can include a compound or composition as describedherein and a label that indicates that the contents are to beadministered to a patient with cancer. In another embodiment, the kitcan include a compound or composition as described herein and a labelthat indicates that the contents are to be administered to a patientwith one or more of hepatocellular carcinoma, colon cancer, leukemia,lymphoma, sarcoma, ovarian cancer, diabetic retinopathy, pulmonaryfibrosis, rheumatoid arthritis, sepsis, ankylosing spondylitis,psoriasis, scleroderma, mycotic and viral infections, bone and cartilagediseases, Alzheimer's disease, lung disease, bone/osteoporotic (wrist,spine, shoulder and hip) fractures, articular cartilage (chondral)defects, degenerative disc disease (or intervertebral discdegeneration), polyposis coli, bone density and vascular defects in theeye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial exudativevitreoretinopathy, retinal angiogenesis, early coronary disease,tetra-amelia, Müllerian-duct regression and virilization, SERKALsyndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease, and Rett syndrome.

Methods of Treatment

The compounds and compositions provided herein can be used as inhibitorsand/or modulators of one or more components of the Wnt pathway, whichmay include one or more Wnt proteins, and thus can be used to treat avariety of disorders and diseases in which aberrant Wnt signaling isimplicated, such as cancer and other diseases associated with abnormalangiogenesis, cellular proliferation, and cell cycling. Accordingly, thecompounds and compositions provided herein can be used to treat cancer,to reduce or inhibit angiogenesis, to reduce or inhibit cellularproliferation, to correct a genetic disorder, and/or to treat aneurological condition/disorder/disease due to mutations ordysregulation of the Wnt pathway and/or of one or more of Wnt signalingcomponents. Non-limiting examples of diseases which can be treated withthe compounds and compositions provided herein include a variety ofcancers, diabetic retinopathy, pulmonary fibrosis, rheumatoid arthritis,scleroderma, mycotic and viral infections, bone and cartilage diseases,neurological conditions/diseases such as Alzheimer's disease,amyotrophic lateral sclerosis (ALS), motor neuron disease, multiplesclerosis or autism, lung disease, bone/osteoporotic (wrist, spine,shoulder and hip) fractures, polyposis coli, bone density and vasculardefects in the eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familialexudative vitreoretinopathy, retinal angiogenesis, early coronarydisease, tetra-amelia, Müllerian-duct regression and virilization,SERKAL syndrome, type II diabetes, Fuhrmann syndrome,Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication, tooth agenesis, Wilms tumor, skeletal dysplasia,focal dermal hypoplasia, autosomal recessive anonychia, neural tubedefects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICFsyndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-WiedemannSyndrome, Norrie disease and Rett syndrome.

With respect to cancer, the Wnt pathway is known to be constitutivelyactivated in a variety of cancers including, for example, colon cancer,hepatocellular carcinoma, lung cancer, ovarian cancer, prostate cancer,pancreatic cancer and leukemias such as CML, CLL and T-ALL. Accordingly,the compounds and compositions described herein may be used to treatthese cancers in which the Wnt pathway is constitutively activated. Incertain embodiments, the cancer is chosen from hepatocellular carcinoma,colon cancer, leukemia, lymphoma, sarcoma and ovarian cancer.

Other cancers can also be treated with the compounds and compositionsdescribed herein.

More particularly, cancers that may be treated by the compounds,compositions and methods described herein include, but are not limitedto, the following:

1) Breast cancers, including, for example ER⁺ breast cancer, ER⁻ breastcancer, her2⁻ breast cancer, her2⁺ breast cancer, stromal tumors such asfibroadenomas, phyllodes tumors, and sarcomas, and epithelial tumorssuch as large duct papillomas; carcinomas of the breast including insitu (noninvasive) carcinoma that includes ductal carcinoma in situ(including Paget's disease) and lobular carcinoma in situ, and invasive(infiltrating) carcinoma including, but not limited to, invasive ductalcarcinoma, invasive lobular carcinoma, medullary carcinoma, colloid(mucinous) carcinoma, tubular carcinoma, and invasive papillarycarcinoma; and miscellaneous malignant neoplasms. Further examples ofbreast cancers can include luminal A, luminal B, basal A, basal B, andtriple negative breast cancer, which is estrogen receptor negative(ER⁻), progesterone receptor negative, and her2 negative (her2⁻). Insome embodiments, the breast cancer may have a high risk Oncotype score.

2) Cardiac cancers, including, for example sarcoma, e.g., angiosarcoma,fibrosarcoma, rhabdomyosarcoma, and liposarcoma; myxoma; rhabdomyoma;fibroma; lipoma and teratoma.

3) Lung cancers, including, for example, bronchogenic carcinoma, e.g.,squamous cell, undifferentiated small cell, undifferentiated large cell,and adenocarcinoma; alveolar and bronchiolar carcinoma; bronchialadenoma; sarcoma; lymphoma; chondromatous hamartoma; and mesothelioma.

4) Gastrointestinal cancer, including, for example, cancers of theesophagus, e.g., squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, and lymphoma; cancers of the stomach, e.g., carcinoma,lymphoma, and leiomyosarcoma; cancers of the pancreas, e.g., ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,and vipoma; cancers of the small bowel, e.g., adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, and fibroma; cancers of the large bowel, e.g.,adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, andleiomyoma.

5) Genitourinary tract cancers, including, for example, cancers of thekidney, e.g., adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma,and leukemia; cancers of the bladder and urethra, e.g., squamous cellcarcinoma, transitional cell carcinoma, and adenocarcinoma; cancers ofthe prostate, e.g., adenocarcinoma, and sarcoma; cancer of the testis,e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, and lipoma.

6) Liver cancers, including, for example, hepatoma, e.g., hepatocellularcarcinoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma;hepatocellular adenoma; and hemangioma.

7) Bone cancers, including, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochrondroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors.

8) Nervous system cancers, including, for example, cancers of the skull,e.g., osteoma, hemangioma, granuloma, xanthoma, and osteitis deformans;cancers of the meninges, e.g., meningioma, meningiosarcoma, andgliomatosis; cancers of the brain, e.g., astrocytoma, medulloblastoma,glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, and congenital tumors;and cancers of the spinal cord, e.g., neurofibroma, meningioma, glioma,and sarcoma.

9) Gynecological cancers, including, for example, cancers of the uterus,e.g., endometrial carcinoma; cancers of the cervix, e.g., cervicalcarcinoma, and pre tumor cervical dysplasia; cancers of the ovaries,e.g., ovarian carcinoma, including serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma, granulosa theca cell tumors,Sertoli Leydig cell tumors, dysgerminoma, and malignant teratoma;cancers of the vulva, e.g., squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, and melanoma; cancers of thevagina, e.g., clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma, and embryonal rhabdomyosarcoma; and cancers of the fallopiantubes, e.g., carcinoma.

10) Hematologic cancers, including, for example, cancers of the blood,e.g., acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, and myelodysplastic syndrome, Hodgkin'slymphoma, non-Hodgkin's lymphoma (malignant lymphoma) and Waldenstrom'smacroglobulinemia.

11) Skin cancers and skin disorders, including, for example, malignantmelanoma and metastatic melanoma, basal cell carcinoma, squamous cellcarcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, and scleroderma.

12) Adrenal gland cancers, including, for example, neuroblastoma.

Cancers may be solid tumors that may or may not be metastatic. Cancersmay also occur, as in leukemia, as a diffuse tissue. Thus, the term“tumor cell,” as provided herein, includes a cell afflicted by any oneof the above identified disorders.

A method of treating cancer using a compound or composition as describedherein may be combined with existing methods of treating cancers, forexample by chemotherapy, irradiation, or surgery (e.g., oophorectomy).In some embodiments, a compound or composition can be administeredbefore, during, or after another anticancer agent or treatment.

The compounds and compositions described herein can be used asanti-angiogenesis agents and as agents for modulating and/or inhibitingthe activity of protein kinases, thus providing treatments for cancerand other diseases associated with cellular proliferation mediated byprotein kinases. For example, the compounds described herein can inhibitthe activity of one or more kinases. Accordingly, provided herein is amethod of treating cancer or preventing or reducing angiogenesis throughkinase inhibition.

In addition, and including treatment of cancer, the compounds andcompositions described herein can function as cell-cycle control agentsfor treating proliferative disorders in a patient. Disorders associatedwith excessive proliferation include, for example, cancers, scleroderma,immunological disorders involving undesired proliferation of leukocytes,and restenosis and other smooth muscle disorders. Furthermore, suchcompounds may be used to prevent de-differentiation of post-mitotictissue and/or cells.

Diseases or disorders associated with uncontrolled or abnormal cellularproliferation include, but are not limited to, the following:

-   -   a variety of cancers, including, but not limited to, carcinoma,        hematopoietic tumors of lymphoid lineage, hematopoietic tumors        of myeloid lineage, tumors of mesenchymal origin, tumors of the        central and peripheral nervous system and other tumors including        melanoma, seminoma and Kaposi's sarcoma.    -   a disease process which features abnormal cellular        proliferation, e.g., benign prostatic hyperplasia, familial        adenomatosis polyposis, neurofibromatosis, atherosclerosis,        arthritis, glomerulonephritis, restenosis following angioplasty        or vascular surgery, inflammatory bowel disease, transplantation        rejection, endotoxic shock, and fungal infections. Fibrotic        disorders such as skin fibrosis; scleroderma; progressive        systemic fibrosis; lung fibrosis; muscle fibrosis; kidney        fibrosis; glomerulosclerosis; glomerulonephritis; hypertrophic        scar formation; uterine fibrosis; renal fibrosis; cirrhosis of        the liver, liver fibrosis; fatty liver disease (FLD); adhesions,        such as those occurring in the abdomen, pelvis, spine or        tendons; chronic obstructive pulmonary disease; fibrosis        following myocardial infarction; pulmonary fibrosis; fibrosis        and scarring associated with diffuse/interstitial lung disease;        central nervous system fibrosis, such as fibrosis following        stroke; fibrosis associated with neuro-degenerative disorders        such as Alzheimer's Disease or multiple sclerosis; fibrosis        associated with proliferative vitreoretinopathy (PVR);        restenosis; endometriosis; ischemic disease and radiation        fibrosis.    -   defective apoptosis-associated conditions, such as cancers        (including but not limited to those types mentioned herein),        viral infections (including but not limited to herpesvirus,        poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus),        prevention of AIDS development in HIV-infected individuals,        autoimmune diseases (including but not limited to systemic lupus        erythematosus, rheumatoid arthritis, sepsis, ankylosing        spondylitis, psoriasis, scleroderma, autoimmune mediated        glomerulonephritis, inflammatory bowel disease and autoimmune        diabetes mellitus), neuro-degenerative disorders (including but        not limited to Alzheimer's disease, lung disease, amyotrophic        lateral sclerosis, retinitis pigmentosa, Parkinson's disease,        AIDS-related dementia, spinal muscular atrophy and cerebellar        degeneration), myelodysplastic syndromes, aplastic anemia,        ischemic injury associated with myocardial infarctions, stroke        and reperfusion injury, arrhythmia, atherosclerosis,        toxin-induced or alcohol related liver diseases, hematological        diseases (including but not limited to chronic anemia and        aplastic anemia), degenerative diseases of the musculoskeletal        system (including but not limited to osteoporosis and        arthritis), tendinopathies such as tendinitis and tendinosis,        aspirin-sensitive rhinosinusitis, cystic fibrosis, multiple        sclerosis, kidney diseases and cancer pain.    -   genetic diseases due to mutations in Wnt signaling components,        such as polyposis coli, bone density and vascular defects in the        eye (Osteoporosis-pseudoglioma Syndrome, OPPG), familial        exudative vitreoretinopathy, retinal angiogenesis, early        coronary disease, tetra-amelia, Müllerian-duct regression and        virilization, SERKAL syndrome, type II diabetes, Fuhrmann        syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,        odonto-onycho-dermal dysplasia, obesity, split-hand/foot        malformation, caudal duplication, tooth agenesis, Wilms tumor,        skeletal dysplasia, focal dermal hypoplasia, autosomal recessive        anonychia, neural tube defects, alpha-thalassemia (ATRX)        syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome,        Prader-Willi syndrome, Beckwith-Wiedemann Syndrome, Norrie        disease and Rett syndrome.

The compounds and compositions described herein can be used to treatneurological conditions, disorders and/or diseases caused by dysfunctionin the Wnt signaling pathway. Non-limiting examples of neurologicalconditions/disorders/diseases which can be treated with the compoundsand compositions provided herein include Alzheimer's disease, aphasia,apraxia, arachnoiditis, ataxia telangiectasia, attention deficithyperactivity disorder, auditory processing disorder, autism,alcoholism, Bell's palsy, bipolar disorder, brachial plexus injury,Canavan disease, carpal tunnel syndrome, causalgia, central painsyndrome, central pontine myelinolysis, centronuclear myopathy, cephalicdisorder, cerebral aneurysm, cerebral arteriosclerosis, cerebralatrophy, cerebral gigantism, cerebral palsy, cerebral vasculitis,cervical spinal stenosis, Charcot-Marie-Tooth disease, Chiarimalformation, chronic fatigue syndrome, chronic inflammatorydemyelinating polyneuropathy (CIDP), chronic pain, Coffin-Lowrysyndrome, complex regional pain syndrome, compression neuropathy,congenital facial diplegia, corticobasal degeneration, cranialarteritis, craniosynostosis, Creutzfeldt-Jakob disease, cumulativetrauma disorder, Cushing's syndrome, cytomegalic inclusion body disease(CIBD), Dandy-Walker syndrome, Dawson disease, de Morsier's syndrome,Dejerine-Klumpke palsy, Dejerine-Sottas disease, delayed sleep phasesyndrome, dementia, dermatomyositis, developmental dyspraxia, diabeticneuropathy, diffuse sclerosis, Dravet syndrome, dysautonomia,dyscalculia, dysgraphia, dyslexia, dystonia, empty sella syndrome,encephalitis, encephalocele, encephalotrigeminal angiomatosis,encopresis, epilepsy, Erb's palsy, erythromelalgia, essential tremor,Fabry's disease, Fahr's syndrome, familial spastic paralysis, febrileseizure, Fisher syndrome, Friedreich's ataxia, fibromyalgia, Foville'ssyndrome, Gaucher's disease, Gerstmann's syndrome, giant cell arteritis,giant cell inclusion disease, globoid cell leukodystrophy, gray matterheterotopia, Guillain-Barre syndrome, HTLV-1 associated myelopathy,Hallervorden-Spatz disease, hemifacial spasm, hereditary spasticparaplegia, heredopathia atactica polyneuritiformis, herpes zosteroticus, herpes zoster, Hirayama syndrome, holoprosencephaly,Huntington's disease, hydranencephaly, hydrocephalus, hypercortisolism,hypoxia, immune-mediated encephalomyelitis, inclusion body myositis,incontinentia pigmenti, infantile phytanic acid storage disease,infantile Refsum disease, infantile spasms, inflammatory myopathy,intracranial cyst, intracranial hypertension, Joubert syndrome, Karaksyndrome, Kearns-Sayre syndrome, Kennedy disease, Kinsbourne syndrome,Klippel Feil syndrome, Krabbe disease, Kugelberg-Welander disease, kuru,Lafora disease, Lambert-Eaton myasthenic syndrome, Landau-Kleffnersyndrome, lateral medullary (Wallenberg) syndrome, Leigh's disease,Lennox-Gastaut syndrome, Lesch-Nyhan syndrome, leukodystrophy, Lewy bodydementia, lissencephaly, locked-in syndrome, Lou Gehrig's disease,lumbar disc disease, lumbar spinal stenosis, Lyme disease,Machado-Joseph disease (Spinocerebellar ataxia type 3), macrencephaly,macropsia, megalencephaly, Melkersson-Rosenthal syndrome, Meniere'sdisease, meningitis, Menkes disease, metachromatic leukodystrophy,microcephaly, micropsia, Miller Fisher syndrome, misophonia,mitochondrial myopathy, Mobius syndrome, monomelic amyotrophy, motorneuron disease, motor skills disorder, Moyamoya disease,mucopolysaccharidoses, multi-infarct dementia, multifocal motorneuropathy, multiple sclerosis, multiple system atrophy, musculardystrophy, myalgic encephalomyelitis, myasthenia gravis, myelinoclasticdiffuse sclerosis, myoclonic Encephalopathy of infants, myoclonus,myopathy, myotubular myopathy, myotonia congenital, narcolepsy,neurofibromatosis, neuroleptic malignant syndrome, lupus erythematosus,neuromyotonia, neuronal ceroid lipofuscinosis, Niemann-Pick disease,O'Sullivan-McLeod syndrome, occipital Neuralgia, occult SpinalDysraphism Sequence, Ohtahara syndrome, olivopontocerebellar atrophy,opsoclonus myoclonus syndrome, optic neuritis, orthostatic hypotension,palinopsia, paresthesia, Parkinson's disease, paramyotonia congenita,paraneoplastic diseases, paroxysmal attacks, Parry-Romberg syndrome,Pelizaeus-Merzbacher disease, periodic paralyses, peripheral neuropathy,photic sneeze reflex, phytanic acid storage disease, Pick's disease,polymicrogyria (PMG), polymyositis, porencephaly, post-polio syndrome,postherpetic neuralgia (PHN), postural hypotension, Prader-Willisyndrome, primary lateral sclerosis, prion diseases, progressivehemifacial atrophy, progressive multifocal leukoencephalopathy,progressive supranuclear palsy, pseudotumor cerebri, Ramsay Huntsyndrome type I, Ramsay Hunt syndrome type II, Ramsay Hunt syndrome typeIII, Rasmussen's encephalitis, reflex neurovascular dystrophy, Refsumdisease, restless legs syndrome, retrovirus-associated myelopathy, Rettsyndrome, Reye's syndrome, rhythmic movement disorder, Romberg syndrome,Saint Vitus dance, Sandhoff disease, schizophrenia, Schilder's disease,schizencephaly, sensory integration dysfunction, septo-optic dysplasia,Shy-Drager syndrome, Sjögren's syndrome, snatiation, Sotos syndrome,spasticity, spina bifida, spinal cord tumors, spinal muscular atrophy,spinocerebellar ataxia, Steele-Richardson-Olszewski syndrome,Stiff-person syndrome, stroke, Sturge-Weber syndrome, subacutesclerosing panencephalitis, subcortical arteriosclerotic encephalopathy,superficial siderosis, Sydenham's chorea, syncope, synesthesia,syringomyelia, tarsal tunnel syndrome, tardive dyskinesia, tardivedysphrenia, Tarlov cyst, Tay-Sachs disease, temporal arteritis, tetanus,tethered spinal cord syndrome, Thomsen disease, thoracic outletsyndrome, tic douloureux, Todd's paralysis, Tourette syndrome, toxicencephalopathy, transient ischemic attack, transmissible spongiformencephalopathies, transverse myelitis, tremor, trigeminal neuralgia,tropical spastic paraparesis, trypanosomiasis, tuberous sclerosis,ubisiosis, Von Hippel-Lindau disease (VHL), Viliuisk Encephalomyelitis(VE), Wallenberg's syndrome, Werdnig, Hoffman disease, west syndrome,Williams syndrome, Wilson's disease and Zellweger syndrome.

The compounds and compositions may also be useful in the inhibition ofthe development of invasive cancer, tumor angiogenesis and metastasis.

In some embodiments, the disclosure provides a method for treating adisease or disorder associated with aberrant cellular proliferation byadministering to a patient in need of such treatment an effective amountof one or more of the compounds of Formula (I), in combination(simultaneously or sequentially) with at least one other agent.

In some embodiments, the disclosure provides a method of treating orameliorating in a patient a disorder or disease selected from the groupconsisting of: cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis(IPF), degenerative disc disease, bone/osteoporotic fractures, bone orcartilage disease, and osteoarthritis, the method comprisingadministering to the patient a therapeutically effective amount of acompound according to claim 1, or a pharmaceutically acceptable saltthereof.

In some embodiments, the pharmaceutical composition comprises atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.

In some embodiments, the method of treats a disorder or disease in whichaberrant Wnt signaling is implicated in a patient, the method comprisesadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disorder or disease is cancer.

In some embodiments, the disorder or disease is systemic inflammation.

In some embodiments, the disorder or disease is metastatic melanoma.

In some embodiments, the disorder or disease is fatty liver disease.

In some embodiments, the disorder or disease is liver fibrosis.

In some embodiments, the disorder or disease is tendon regeneration.

In some embodiments, the disorder or disease is diabetes.

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is diabetic retinopathy.

In some embodiments, the disorder or disease is pulmonary fibrosis.

In some embodiments, the disorder or disease is idiopathic pulmonaryfibrosis (IPF).

In some embodiments, the disorder or disease is degenerative discdisease.

In some embodiments, the disorder or disease is rheumatoid arthritis.

In some embodiments, the disorder or disease is scleroderma.

In some embodiments, the disorder or disease is a mycotic or viralinfection.

In some embodiments, the disorder or disease is a bone or cartilagedisease.

In some embodiments, the disorder or disease is Alzheimer's disease.

In some embodiments, the disorder or disease is osteoarthritis.

In some embodiments, the disorder or disease is lung disease

In some embodiments, the disorder or disease is a genetic disease causedby mutations in Wnt signaling components, wherein the genetic disease isselected from: polyposis coli, osteoporosis-pseudoglioma syndrome,familial exudative vitreoretinopathy, retinal angiogenesis, earlycoronary disease, tetra-amelia syndrome, Müllerian-duct regression andvirilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmannsyndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome,odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation,caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletaldysplasia, focal dermal hypoplasia, autosomal recessive anonychia,neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile Xsyndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome,Beckwith-Wiedemann Syndrome, Norrie disease and Rett syndrome.

In some embodiments, the patient is a human.

In some embodiments, the cancer is chosen from: hepatocellularcarcinoma, colon cancer, breast cancer, pancreatic cancer, chronicmyeloid leukemia (CML), chronic myelomonocytic leukemia, chroniclymphocytic leukemia (CLL), acute myeloid leukemia, acute lymphocyticleukemia, Hodgkin lymphoma, lymphoma, sarcoma and ovarian cancer.

In some embodiments, the cancer is chosen from: lung cancer—non-smallcell, lung cancer—small cell, multiple myeloma, nasopharyngeal cancer,neuroblastoma, osteosarcoma, penile cancer, pituitary tumors, prostatecancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer—basal and squamous cell, skin cancer—melanoma, small intestinecancer, stomach (gastric) cancers, testicular cancer, thymus cancer,thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer,laryngeal or hypopharyngeal cancer, kidney cancer, Kaposi sarcoma,gestational trophoblastic disease, gastrointestinal stromal tumor,gastrointestinal carcinoid tumor, gallbladder cancer, eye cancer(melanoma and lymphoma), Ewing tumor, esophagus cancer, endometrialcancer, colorectal cancer, cervical cancer, brain or spinal cord tumor,bone metastasis, bone cancer, bladder cancer, bile duct cancer, analcancer and adrenal cortical cancer.

In some embodiments, the cancer is hepatocellular carcinoma.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is chronic myeloid leukemia (CML).

In some embodiments, the cancer is chronic myelomonocytic leukemia.

In some embodiments, the cancer is chronic lymphocytic leukemia (CLL).

In some embodiments, the cancer is acute myeloid leukemia.

In some embodiments, the cancer is acute lymphocytic leukemia.

In some embodiments, the cancer is Hodgkin lymphoma.

In some embodiments, the cancer is lymphoma.

In some embodiments, the cancer is sarcoma.

In some embodiments, the cancer is ovarian cancer.

In some embodiments, the cancer is lung cancer—non-small cell.

In some embodiments, the cancer is lung cancer—small cell.

In some embodiments, the cancer is multiple myeloma.

In some embodiments, the cancer is nasopharyngeal cancer.

In some embodiments, the cancer is neuroblastoma.

In some embodiments, the cancer is osteosarcoma.

In some embodiments, the cancer is penile cancer.

In some embodiments, the cancer is pituitary tumors.

In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is retinoblastoma.

In some embodiments, the cancer is rhabdomyosarcoma.

In some embodiments, the cancer is salivary gland cancer.

In some embodiments, the cancer is skin cancer—basal and squamous cell.

In some embodiments, the cancer is skin cancer—melanoma.

In some embodiments, the cancer is small intestine cancer.

In some embodiments, the cancer is stomach (gastric) cancers.

In some embodiments, the cancer is testicular cancer.

In some embodiments, the cancer is thymus cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is uterine sarcoma.

In some embodiments, the cancer is vaginal cancer.

In some embodiments, the cancer is vulvar cancer.

In some embodiments, the cancer is Wilms tumor.

In some embodiments, the cancer is laryngeal or hypopharyngeal cancer.

In some embodiments, the cancer is kidney cancer.

In some embodiments, the cancer is Kaposi sarcoma.

In some embodiments, the cancer is gestational trophoblastic disease.

In some embodiments, the cancer is gastrointestinal stromal tumor.

In some embodiments, the cancer is gastrointestinal carcinoid tumor.

In some embodiments, the cancer is gallbladder cancer.

In some embodiments, the cancer is eye cancer (melanoma and lymphoma).

In some embodiments, the cancer is Ewing tumor.

In some embodiments, the cancer is esophagus cancer.

In some embodiments, the cancer is endometrial cancer.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is cervical cancer.

In some embodiments, the cancer is brain or spinal cord tumor.

In some embodiments, the cancer is bone metastasis.

In some embodiments, the cancer is bone cancer.

In some embodiments, the cancer is bladder cancer.

In some embodiments, the cancer is bile duct cancer.

In some embodiments, the cancer is anal cancer.

In some embodiments, the cancer is adrenal cortical cancer.

In some embodiments, the disorder or disease is a neurologicalcondition, disorder or disease, wherein the neurologicalcondition/disorder/disease is selected from: Alzheimer's disease,frontotemporal dementias, dementia with lewy bodies, prion diseases,Parkinson's disease, Huntington's disease, progressive supranuclearpalsy, corticobasal degeneration, multiple system atrophy, amyotrophiclateral sclerosis (ALS), inclusion body myositis, autism, degenerativemyopathies, diabetic neuropathy, other metabolic neuropathies, endocrineneuropathies, orthostatic hypotension, multiple sclerosis andCharcot-Marie-Tooth disease.

In some embodiments, the compound of Formula (I) inhibits one or moreproteins in the Wnt pathway.

In some embodiments, the compound of Formula (I) inhibits signalinginduced by one or more Wnt proteins.

In some embodiments, the Wnt proteins are chosen from: WNT1, WNT2,WNT2B, WNT3, WNT3A, WNT4. WNT5A, WNT5B, WNT6, WNT7A, WNT7B, WNT8A,WNT8B, WNT9A, WNT9B, WNT10A, WNT10B, WNT11, and WNT16.

In some embodiments, the compound of Formula (I) inhibits a kinaseactivity.

In some embodiments, the method treats a disease or disorder mediated bythe Wnt pathway in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) inhibits one or moreWnt proteins.

In some embodiments, the method treats a disease or disorder mediated bykinase activity in a patient, the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the disease or disorder comprises tumor growth,cell proliferation, or angiogenesis.

In some embodiments, the method inhibits the activity of a proteinkinase receptor, the method comprises contacting the receptor with aneffective amount of a compound (or compounds) of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient; the method comprisesadministering to the patient a therapeutically effective amount of acompound (or compounds) of Formula (I), or a pharmaceutically acceptablesalt thereof.

In some embodiments, the method prevents or reduces angiogenesis in apatient; the method comprises administering to the patient atherapeutically effective amount of a compound (or compounds) of Formula(I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method prevents or reduces abnormal cellularproliferation in a patient; the method comprises administering to thepatient a therapeutically effective amount of a compound (or compounds)of Formula (I), or a pharmaceutically acceptable salt thereof.

In some embodiments, the method treats a disease or disorder associatedwith aberrant cellular proliferation in a patient, the method comprisesadministering to the patient a pharmaceutical composition comprising oneor more of the compounds of claim 1 in combination with apharmaceutically acceptable carrier and one or more other agents.

Moreover, the compounds and compositions, for example, as inhibitors ofthe cyclin-dependent kinases (CDKs), can modulate the level of cellularRNA and DNA synthesis and therefore are expected to be useful in thetreatment of viral infections such as HIV, human papilloma virus, herpesvirus, Epstein-Barr virus, adenovirus, Sindbis virus, pox virus and thelike.

Compounds and compositions described herein can inhibit the kinaseactivity of, for example, CDK/cyclin complexes, such as those active inthe G₀. or G_(0.1) stage of the cell cycle, e.g., CDK2, CDK4, and/orCDK6 complexes.

Evaluation of Biological Activity

The biological activity of the compounds described herein can be testedusing any suitable assay known to those of skill in the art, see, e.g.,WO 2001/053268 and WO 2005/009997. For example, the activity of acompound may be tested using one or more of the test methods outlinedbelow.

In one example, tumor cells may be screened for Wnt independent growth.In such a method, tumor cells of interest are contacted with a compound(i.e. inhibitor) of interest, and the proliferation of the cells, e.g.by uptake of tritiated thymidine, is monitored. In some embodiments,tumor cells may be isolated from a candidate patient who has beenscreened for the presence of a cancer that is associated with a mutationin the Wnt signaling pathway. Candidate cancers include, withoutlimitation, those listed above.

In another example, one may utilize in vitro assays for Wnt biologicalactivity, e.g. stabilization of β-catenin and promoting growth of stemcells. Assays for biological activity of Wnt include stabilization ofβ-catenin, which can be measured, for example, by serial dilutions of acandidate inhibitor composition. An exemplary assay for Wnt biologicalactivity contacts a candidate inhibitor with cells containingconstitutively active Wnt/β-catenin signaling. The cells are culturedfor a period of time sufficient to stabilize β-catenin, usually at leastabout 1 hour, and lysed. The cell lysate is resolved by SDS PAGE, thentransferred to nitrocellulose and probed with antibodies specific forβ-catenin.

In a further example, the activity of a candidate compound can bemeasured in a Xenopus secondary axis bioassay (Leyns, L. et al. Cell(1997), 88(6), 747-756).

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.

EXAMPLES

Compound Preparation

The starting materials used in preparing the compounds of the inventionare known, made by known methods, or are commercially available. It willbe apparent to the skilled artisan that methods for preparing precursorsand functionality related to the compounds claimed herein are generallydescribed in the literature. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March's AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure 7^(th) Ed., JohnWiley & Sons (2013), Carey and Sundberg, Advanced Organic Chemistry5^(th) Ed., Springer (2007), Comprehensive Organic Transformations: AGuide to Functional Group Transformations, 2^(nd) Ed., John Wiley & Sons(1999) (incorporated herein by reference in its entirety) and the like.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

(¹H) nuclear magnetic resonance spectra (NMR) were measured in theindicated solvents on a Bruker NMR spectrometer (Avance™ DRX300, 300 MHzfor ¹H or Avance™ DRX500, 500 MHz for ¹H) or Varian NMR spectrometer(Mercury 400BB, 400 MHz for ¹H). Peak positions are expressed in partsper million (ppm) downfield from tetramethylsilane. The peakmultiplicities are denoted as follows, s, singlet; d, doublet; t,triplet; q, quartet; ABq, AB quartet; quin, quintet; sex, sextet; sep,septet; non, nonet; dd, doublet of doublets; ddd, doublet of doublets ofdoublets; d/ABq, doublet of AB quartet; dt, doublet of triplets; td,triplet of doublets; dq, doublet of quartets; m, multiplet.

The following abbreviations have the indicated meanings:

Boc=tert-butyloxycarbonyl

brine=saturated aqueous sodium chloride

CDCl₃=deuterated chloroform

CuI=copper (I) iodide or cuprous iodide

DCE=dichloroethane

DCM=dichloromethane

DIPEA=N,N-diisopropylethylamine

DMAP=4-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

DMSO-d₆=deuterated dimethylsulfoxide

ESIMS=electron spray mass spectrometry

EtOAc=ethyl acetate

HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate

HCl=hydrochloric acid

HOAc=acetic acid

LC/MS=Liquid chromatography-mass spectrometry

MeCN=acetonitrile

MeOH=methanol

MgSO₄=magnesium sulfate

NaBH(OAc)₃=sodium triacetoxyborohydride

NMR=nuclear magnetic resonance

ON=overnight

Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride

Pd(PPh₃)₄=tetrakis(triphenylphosphine)palladium(0)

r.t.=room temperature

THF=tetrahydrofuran

TLC=thin layer chromatography

pTsO-=p-toluenesulfonate ester

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds of the invention will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. The skilled artisan is thoroughly equipped to prepare thesecompounds by those methods given the literature and this disclosure. Thecompound numberings used in the synthetic schemes depicted below aremeant for those specific schemes only, and should not be construed as orconfused with same numberings in other sections of the application.Unless otherwise indicated, all variables are as defined above.

General Procedure

Compounds of Formula I of the present disclosure can be prepared asdepicted in Scheme 1.

Scheme 1 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IX) by first coupling the aminewith a variety of acids (III) to produce amide IV. The bromo derivativeIV is then reacted with bis(pinacolato)diboron to give the pinacol ester(V). Suzuki coupling with a variety of 5-membered heteroaryl bromides(VIII) yields the desired R³ substituted isoquinoline IX. Alternatively,the bromo derivative IV is Suzuki coupled with a variety of 5-memberedheteroaryl pinacol esters (VI) or coupled to a variety of 5-memberedheteroaryl stannanes (VII) to produce the final R³ substitutedisoquinoline IX.

In some embodiments, compounds of Formula I of the present disclosurecan be prepared as depicted in Scheme 2.

Scheme 2 describes a method for preparation ofisoquinoline-3-carboxamide derivatives (IXa) starting with bromointermediate IV and couple with the nitrogen of a variety of R³ NHheteroaryls to produce the final R³ substituted isoquinoline IXa.

Illustrative Compound Examples Preparation of Intermediate2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy) isonicotinic acid (XII)is depicted below in Scheme 4

Step 1

To a solution of 2-fluoropyridine-4-carboxylic acid (X) (6.65 g, 47.13mmol) in DMSO (180 mL) was added tert-butyl4-hydroxypiperidine-1-carboxylate (XI) (14.23 g, 70.69 mmol) and2-fluoropyridine-4-carboxylic acid (6.65 g, 47.13 mmol). To this mixturewas added NaH (8.48 g, 212.08 mmol) in 3 portions. this mixture wasstirred at room temperature for 48 h. The reaction was poured into 1 NNaOH, the water layer was washed with EtOAc, the water layer was thenacidified with concentrated HCl (20 mL), extracted with EtOAc and driedover Na₂SO₄. The solvent was removed and the residue was purified by C18Silica Gel column chromatography (0-40% MeCN/0.1% formic acid in water)to produce 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isonicotinicacid (XII) (12.85 g, 39.9 mmol, 84.6% yield) as a white solid. ¹H NMR(499 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H), 1.52-1.62 (m, 2H), 1.90-1.98 (m,2H), 3.12-3.23 (m, 2H), 3.64-3.72 (m, 2H), 5.21 (tt, J=8.13, 3.95 Hz,1H), 7.15 (s, 1H), 7.36 (dd, J=5.21, 1.37 Hz, 1H), 8.31 (d, J=5.21 Hz,1H), 13.62 (br s, 1H); ESIMS found for C₁₆H₂₂N₂O₅ m/z 323.1 (M+H).

Preparation of Intermediate4-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy) benzoic acid (XV) isDepicted Below in Scheme 5

Step 1

To a solution of DEAD (12.3 mL, 27.08 mmol) (40% in toluene) was addedto a mixture of ethyl 4-hydroxybenzoate (XIII) (3.0 g, 18.05 mmol),tert-butyl 4-hydroxypiperidine-1-carboxylate (XI) (4.72 g, 23.47 mmol)and triphenylphosphane (6.16 g, 23.47 mmol) in THF (40 mL) at 0° C. Themixture was stirred from 0° C. to room temperature over 1 day beforeconcentrating in vacuo. The residue was diluted with EtOAc, washed with1 N NaOH and brine, and then evaporated under vacuum. The crude productwas purified by chromatography (0→30% EtOAc/hexanes) to give tert-butyl4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (XIV) (5.4 g, 15.45mmol, 85.6% yield) as a colorless oil. ESIMS found for C₁₉H₂₇NO₅ m/z372.1 (M+Na).

Step 2

To a solution of tert-butyl4-(4-ethoxycarbonylphenoxy)piperidine-1-carboxylate (XIV) (5.4 g, 15.45mmol) in MeOH (10 mL) and THF (10 mL) was added LiOH (15.5 mL, 61.82mmol) and the mixture stirred at 60° C. for 2 h. The mixture wasconcentrated and the residue triturated with water. The resultingsolution was acidified with 2 N HCl until a solid precipitated. Thesolid was filtered and washed with water to afford4-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]benzoic acid (XV) (4.7 g,14.63 mmol, 94.6% yield) as a white solid. ¹H NMR (499 MHz, DMSO-d₆) δppm 1.40 (9H, s), 1.47-1.57 (2H, m), 1.89-1.97 (2H, m), 3.12-3.23 (2H,m), 3.63-3.70 (2H, m), 4.63-4.71 (1H, m), 7.04 (2H, d, J=9.06 Hz), 7.87(2H, d, J=9.06 Hz); ESIMS found for C₁₇H₂₃NO₅ m/z 344.1 (M+Na).

Preparation of Intermediate1-(methyl-d₃)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(XVII) is Depicted Below in Scheme 6

Step 1

To a stirred suspension of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (XVI) (1.435g, 7.4 mmol) and Cs₂CO₃ (2.89 g, 8.87 mmol) in DMF (15 mL) was addedtrideuterio(iodo)methane (0.51 mL, 8.13 mmol) and the mixture wasstirred at room temperature overnight. The reaction mixture was filteredand the filtrates were concentrated and dried under high vacuo to obtain4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteriomethyl)pyrazole (XVII) (3.9 g, 18.48 mmol, 249.8% yield) as a white solid whichwas used for next step without purification. ESIMS found forC₁₀H₁₄[²H₃]BN₂O₂ m/z 212. (M+1).

Preparation of Intermediate 6-bromoisoquinolin-1-d-3-amine (XIX) isDepicted Below in Scheme 8

Step 1

To a mixture of 1,6-dibromoisoquinolin-3-amine (XVIII) (0.5 g, 1.66mmol), ammonium formate-d₅ (0.56 g, 8.28 mmol) and Pd(PPh₃)₄ (191.3 mg,0.170 mmol) in DMF (5 mL) was heated to 50° C. for 48 h. The solventswere concentrated and the residue was suspended in chloroform. The solidwas collected by filtration and washed with water and EtOAc. The solidwere dried under high vacuo to obtain6-bromo-1-deuterio-isoquinolin-3-amine (XIX) (115 mg, 0.513 mmol, 31.0%yield) as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 6.11 (2H,s), 6.55 (1H, s), 7.22 (1H, dd, J=8.78, 1.92 Hz), 7.73 (1H, d, J=8.51Hz), 7.79 (1H, d, J=1.92 Hz); ESIMS found for C₉H₆DBrN₂ m/z 224.0(⁷⁹BrM+H).

Preparation of Intermediate 6-bromo-4-chloroisoquinolin-3-amine (XXII)is Depicted Below in Scheme 9

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XX) (1.0 g, 4.48mmol) in DMF (15 mL) at 0° C. was added 1-chloropyrrolidine-2,5-dione(XXI) (598.6 mg, 4.48 mmol) portionwise. The mixture was stirred at 0°C. for 6 h. The reaction mixture was added to water (150 mL), stirredfor 1 h and the resulting solids were collected by filtration and airdried overnight to obtain 6-bromo-4-chloro-isoquinolin-3-amine (XXII)(922 mg, 3.58 mmol, 79.9% yield) as a beige solid which was used fornext step without purification. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.55(2H, s), 7.40 (1H, dd, J=8.64, 1.78 Hz), 7.88 (1H, d, J=8.51 Hz), 7.90(1H, d, J=1.10 Hz), 8.86 (1H, s); ESIMS found for C₉H₆BrClN₂ m/z 256.9(⁷⁹BrM+H).

Preparation of Intermediate 6-bromo-4-methylisoquinolin-3-amine (XXV) isDepicted Below in Scheme 10

Step 1

To a stirred suspension of 6-bromoisoquinolin-3-amine (XX) (2. g, 8.97mmol) in DMF (25.1 mL) at 0° C. was added 1-iodopyrrolidine-2,5-dione(XXIII) (2.02 g, 8.97 mmol) portionwise, The mixture was stirred at 0°C. for 1 hr. LC-MS of the mixture showed completion of the reaction andthe desired product. The solvent was removed under vacuum, the residuewas purified by C₁₈ Silica gel (240 g) [0→100% H₂O/MeCN (0.1% Formicacid)] to produce 6-bromo-4-iodo-isoquinolin-3-amine (XXIV) (1.95 g,5.58 mmol, 62.2% yield) as a brown solid. ¹H NMR (499 MHz, DMSO-d₆) δppm 6.41 (2H, br s), 7.40 (1H, dd, J=8.64, 1.78 Hz), 7.76-7.81 (1H, m),7.82 (1H, d, J=8.51 Hz), 8.81 (1H, s); ESIMS found for C₉H₆BrIN₂ m/z348.9 (⁷⁹BrM+H).

Step 2

A stirred solution of 6-bromo-4-iodo-isoquinolin-3-amine (XXIV) (1.0 g,2.87 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.72 g, 2.87mmol), Pd(dppf)Cl₂ (0.23 g, 0.29 mmol), and K₃PO₄ (5.73 mL, 5.73 mmol)in 1,4-dioxane (10 mL) was heated to 90° C. for 3 days. The solvent wasremoved under high vacuum and the residue was purified by C18 silica gel(240 g) [0→20% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-4-methyl-isoquinolin-3-amine (XXV) (74 mg, 0.312 mmol, 10.9%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.23 (3H,br s), 5.91 (2H, br s), 7.27 (1H, br d, J=2.20 Hz), 7.71-7.82 (1H, m),7.92 (1H, br s), 8.72 (1H, br s); ESIMS found for C₁₀H₉BrN₂ m/z 239.0(⁸¹BrM+H).

Preparation of Intermediate 6-bromo-7-fluoroisoquinolin-3-amine (XXVIII)is Depicted Below in Scheme 11

Step 1

To a vial was added 2,2-diethoxyacetonitrile (XXVI) (1.0 g, 7.74 mmol)dissolved MeOH (7.74 mL) followed by addition of MeONa/MeOH (0.18 mL,0.77 mmol) dropwise. The reaction was stirred at room temperature for 20h. HOAc (44.3 μL, 0.77 mmol) was added until pH=7-8 (using pH strips).(4-Bromo-3-fluoro-phenyl)methanamine hydrochloride (XXVII) (1.86 g, 7.74mmol) was added and stirred at 40° C. for 4 h. The solvent was removedunder vacuum. Sulfuric acid (12.6 mL, 232.3 mmol) was added and stirredat 40° C. for 16 h. NH₄OH (30.8 mL, 240.0 mmol) was added dropwise at 0°C. The solvent was removed under vacuum and the residue was purified byC₁₈ silica gel (240 g) [0→50% H₂O/MeCN (0.1% Formic acid)] to produce6-bromo-7-fluoro-isoquinolin-3-amine (XXVIII) (1.33 g, 5.50 mmol, 71.1%yield) as an off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 6.07 (2H,s), 6.61 (1H, s), 7.76 (1H, d, J=9.33 Hz), 8.01 (1H, d, J=6.86 Hz), 8.80(1H, s); ESIMS found for C₉H₆BrFN₂ m/z 242.9 (⁸¹BrM+H).

Preparation of Intermediates 6-bromo-7-chloroisoquinolin-3-amine (XXX)and 6-bromo-5-chloroisoquinolin-3-amine (XXXI) is depicted below inScheme 12

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XXVI) (0.59 g, 4.57mmol) in a vial containing MeOH (4.57 mL) was added MeONa (0.1 mL, 0.46mmol) dropwise. The reaction was stirred at 35° C. for 20 h. HOAc wasadded (26.1 μL, 0.46 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-chloro-phenyl)methanamine (XXIX) (1.01 g, 4.57mmol). The mixture was stirred at 35° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (7.43 mL, 137.0 mmol) was then addedand stirred at 35° C. for 16 h. NH₄OH (60.6 mL, 141.6 mmol) was added at0° C. The reaction was filtered through Celite and purified by C₁₈silica gel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1mixture (by nmr) of 6-bromo-7-chloro-isoquinolin-3-amine (XXX) and6-bromo-5-chloroisoquinolin-3-amine (XXXI) (633.7 mg, 2.46 mmol, 53.9%yield). ¹H NMR (499 MHz, DMSO-d6) δ ppm 6.23 (2H, s), 6.46 (2H, s), 6.57(1H, s), 6.83 (1H, s), 7.40 (1H, d, J=8.51 Hz), 7.74 (1H, d, J=8.51 Hz),8.05 (1H, s), 8.09 (1H, s), 8.81 (1H, s), 8.88 (1H, s); ESIMS found forC₉H₆BrClN₂ m/z 256.9 (⁷⁹BrM+H).

Preparation of Intermediates 6-bromo-7-methylisoquinolin-3-amine(XXXIII) and 6-bromo-5-methylisoquinolin-3-amine (XXXIV) is DepictedBelow in Scheme 13

Step 1

To a stirred solution of 2,2-diethoxyacetonitrile (XXVI) (0.33 g, 2.52mmol) in a vial containing MeOH (2.52 mL) was added MeONa (0.23 mL, 0.25mmol) dropwise. The reaction was stirred at 22° C. for 20 h. HOAc wasadded (14.4 μL, 0.25 mmol) (checked that the pH is 7-8 using pH strips)followed by (4-bromo-3-methyl-phenyl)methanamine (XXXII) (0.5 g, 2.52mmol). The mixture was stirred at 40° C. for 40 h. The solvent wasremoved under vacuum. Sulfuric Acid (4.09 mL, 75.49 mmol) was then addedand stirred at 40° C. for 16 h. NH₄OH (33.4 mL, 78 mmol) was added at 0°C. The reaction was filtered through Celite and purified by C₁₈ silicagel (240 g) [0→30% H₂O/MeCN (0.1% Formic acid)] to produce a 1:1 mixture(by nmr) of 6-bromo-7-methylisoquinolin-3-amine (XXXIII) and6-bromo-5-methylisoquinolin-3-amine (XXXIV) (378 mg, 1.59 mmol, 63.4%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.40 (3H, s), 2.52 (3H, s), 5.96(2H, s), 6.12 (1H, s), 6.54 (1H, s), 6.71 (1H, s), 7.27 (1H, d, J=8.78Hz), 7.58 (1H, d, J=8.78 Hz), 7.73 (1H, s), 7.86 (1H, s), 8.74 (1H, s),8.79 (1H, s); ESIMS found for C₁₀H₉BrN₂ m/z 237.0 (⁷⁹BrM+H).

Example 1 Preparation of4-(difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide (29) is Depicted Below in Scheme 14

Step 1

A mixture of 4-(difluoromethoxy)benzoic acid (XXXV) (337 mg, 1.79 mmol),HATU (682 mg, 1.79 mmol) and DIPEA (0.47 mL, 2.69 mmol) in DCE (8 mL)was stirred at room temperature for 10 min. To the above mixture wasadded 6-bromoisoquinolin-3-amine (XX) (200 mg, 0.900 mmol) and DMAP (110mg, 0.900 mmol) and the resulting mixture was stirred at 80° C. for 17h. The reaction was poured into 1 N HCl and extracted with DCM (2×). Thecombined organic layers were dried, filtered and concentrated. The crudeproduct was purified by silica gel chromatography with EtOAc/Hexanes(0→25%) as the eluent to affordN-(6-bromoisoquinolin-3-yl)-4-(difluoromethoxy)benzamide (XXXVI) as awhite solid (300 mg, 0.763 mmol, 85.1% yield). ESIMS found forC₁₇H₁₁BrF₂N₂O₂ m/z 395.0 (M^(Br81)+H).

Step 2

A mixture of N-(6-bromoisoquinolin-3-yl)-4-(difluoromethoxy)benzamide(XXXVI) (100 mg, 0.250 mmol) tributyl-(3-methylimidazol-4-yl)stannane(XXXVII) (104 mg, 0.280 mmol) Pd(PPh₃)₄ (23 mg, 0.030 mmol) and CuI (5mg, 0.030 mmol) was taken in DMF (2 mL). N₂ gas was bubbled into themixture for 10 min and then heated at 90° C. for 21 h. The reactionmixture was cooled to room temperature, concentrated, absorbed on silicagel and purified by flash column chromatography using 7 N NH₃-MeOH/CHCl₃(0 to 10%) as eluents. The pure fractions were concentrated, the residuesuspended in diethyl ether, sonicated and the resulting solids werecollected by filtration, and dried to obtain4-(difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide(29) as a white solid (16 mg, 0.040 mmol, 15.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (s, 3H), 7.40 (t, J=73.65 Hz, 1H), 7.32 (d, J=8.78Hz, 2H), 7.33 (br s, 1H), 7.73 (dd, J=8.37, 1.51 Hz, 1H), 7.81 (s, 1H),8.09 (s, 1H), 8.15 (d, J=8.51 Hz, 1H), 8.17 (d, J=8.78 Hz, 2H), 8.69 (s,1H), 9.22 (s, 1H), 10.96 (s, 1H); ESIMS found for C₂₁H₁₆F₂N₄O₂ m/z 395.1(M+1).

Example 2 Preparation of2-(4-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide (53) and2-(4-(dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide(55) are Depicted Below in Scheme 15

Step 1

To a solution Added 2-fluoropyridine-4-carboxylic acid (XXXVIII) (1.27g, 8.97 mmol), HATU (1.7 g, 4.48 mmol), DMAP (0.55 g, 4.48 mmol) and6-bromoisoquinolin-3-amine (XX) (1.0 g, 4.48 mmol) to MeCN (22.4 mL)followed by DIPEA (3.12 mL, 17.93 mmol) at room temperature then stirredat stirred at 60° C. for 90 min. One additional eq of HATU (1.7 g, 4.48mmol) was added and the reaction was stirred overnight. Another 0.05 eqHATU was added and stirred for another 1 h. The reaction was poured into300 mL of water, the solid was filtered and washed with MeOH, to produceN-(6-bromoisoquinolin-3-yl)-2-fluoroisonicotinamide (XXXIX) as anoff-white solid (1.38 g, 3.99 mmol, 89.0% yield). ESIMS found forC₁₅H₉BrFN₃O m/z 346.2 (M+H).

Step 2

To a suspension of N-(6-bromoisoquinolin-3-yl)-2-fluoroisonicotinamide(XXXIX) (300 mg, 0.870 mmol) in MeCN (4.3 mL) was added tert-butylN-(4-piperidyl)carbamate (XL) (868 mg, 4.33 mmol). The mixture washeated at reflux for 1 day and then cooled to room temperature. Thereaction was concentrated in vacuo and purified by silica gel (24 g) 0to 100% EtOAc/hexanes to produce tert-butyl(1-(4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate (XLI) as an off-white solid (0.319 g, 0.606 mmol, 69.9%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.31-1.45 (m, 2H), 1.39 (s, 9H),1.80 (br d, J=10.43 Hz, 2H), 2.97 (br t, J=11.53 Hz, 2H), 3.49-3.60 (m,1H), 4.35 (br d, J=13.17 Hz, 2H), 6.85 (br d, J=7.41 Hz, 1H), 7.10 (dd,J=5.08, 1.23 Hz, 1H), 7.46 (s, 1H), 7.70 (dd, J=8.78, 1.92 Hz, 1H), 8.07(d, J=8.78 Hz, 1H), 8.24 (d, J=4.94 Hz, 1H), 8.29 (d, J=1.37 Hz, 1H),8.61 (s, 1H), 9.25 (s, 1H), 11.16 (s, 1H); ESIMS found for C₂₅H₂₈BrN₅O₃m/z 528.1 (M^(Br81)+H).

Step 3

To a solution of tert-butyl (1-(4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate (XLI) (95.0 mg, 0.220 mmol) in1,4-dioxane (6.0 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(XLII) (55.6 mg, 0.270 mmol), K₃PO₄ (210 mg, 0.990 mmol), andPd(dppf)Cl₂ (0.05 g, 0.060 mmol). The mixture was degassed with Argonand heated to 90° C. for 16 h. The solvent was removed under vacuum andthe residue was purified by silica gel (220 g) using 0 to 10% 1.7 N NH₃in CHCl₃. The solid was tritrated with diethyl ether and placed undervacuum overnight, then tritrated with hot ethanol and dried in a vacuumoven at 50° C. to produce tert-butyl(1-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate(XLIII) as an off-white solid (294 . . . 4 mg, 0.558 mmol, 93.0% yield).ESIMS found for C₂₉H₃₃N₇O₃ m/z 528.3 (M+H).

Step 4

To a solution of tert-butyl(1-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperidin-4-yl)carbamate(XLIII) (294.0 mg, 0.560 mmol) in MeOH (5.6 mL) was added HCl (1.39 mL,5.57 mmol). The reaction was stirred at 60° C. for 1 h. The solvent wasremoved under vacuum and the residue was purified by silica gel (24 g)using 0 to 10% 1.7 N NH₃ in MeOH to produce2-(4-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide(53) as an off-white solid (195 mg, 0.456 mmol, 81.9% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 1.20-1.29 (m, 2H), 1.76-1.83 (m, 2H), 2.82-2.90(m, 1H), 2.93-3.02 (m, 2H), 3.91 (s, 3H), 4.32 (br d, J=13.17 Hz, 2H),7.10 (dd, J=5.21, 1.10 Hz, 1H), 7.45 (s, 1H), 7.81 (dd, J=8.51, 1.65 Hz,1H), 8.07 (d, J=8.78 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.23 (d,J=4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.03 (br s,1H); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

Step 5

To a solution of2-(4-aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide(53) (90.0 mg, 0.210 mmol) in DCM (2.1 mL) was added formaldehyde (170.9mg, 2.11 mmol), HOAc (2.5 mg, 0.042 mmol) and NaBH(OAc)₃ (178.5 mg,0.840 mmol). The reaction was stirred at room temperature for 16 h. Thesolvent was removed under vacuum and the residue was purified by silicagel (12 g) using 0 to 30% 1.7N NH₃ in MeOH/CHCl₃ to produce2-[4-(dimethylamino)-1-piperidyl]-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(55) as an off-white solid (30.0 mg, 0.066 mmol, 31.3% yield). ¹H NMR(499 MHz, DMSO-d₆) δ ppm 1.37 (qd, J=11.94, 3.70 Hz, 2H), 1.83 (br d,J=11.25 Hz, 2H), 2.19 (s, 6H), 2.30-2.40 (m, 1H), 2.84-2.93 (m, 2H),3.91 (s, 3H), 4.44 (br d, J=13.17 Hz, 2H), 7.11 (dd, J=5.21, 1.10 Hz,1H), 7.45 (s, 1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.07 (d, J=8.51 Hz,1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.24 (d, J=5.21 Hz, 1H), 8.38 (s, 1H),8.59 (s, 1H), 9.12 (s, 1H), 11.03 (s, 1H); ESIMS found for C₂₆H₂₉N₇O m/z456.2 (M+1).

Example 3 Preparation ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide(16) andN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide(17) are Depicted Below in Scheme 16

Step 1

To a solution of 6-bromoisoquinolin-3-amine (XX) (3.0 g, 13.45 mmol) and2-((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)isonicotinic acid (XII)(10.62 g, 32.94 mmol) in DCE was added DMAP (1.64 g, 13.45 mmol), DIPEA(7.03 mL, 40.35 mmol), HATU (12.32 g, 32.4 mmol) to DCE (67.2 mL)stirred at 75° C. for 16 hours. The solvent was removed under vacuum andpurified by silica gel (40 g) using 0 to 50% EtOAc/hexanes to producetert-butyl4-((4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate(XLIV) as an off-white solid (4.37 g, 8.29 mmol, 61.6% yield). ESIMSfound for C₂₅H₂₇BrN₄O₄ m/z 426.1 (M-Boc).

Step 2

To a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(XLII) (2.59 g, 12.43 mmol) in 1,4-dioxane (82.8 mL) was addedtert-butyl4-((4-((6-bromoisoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate(XLIV) (4.37 g, 8.29 mmol), K₃PO₄ (4.4 g, 20.7 mmol) and Pd(dppf)Cl₂(338.3 mg, 0.410 mmol). The mixture was degassed with Ar and heated to90° C. for 16 h. The solvent was removed under vacuum and the residuewas purified by silica ge (120 g) using 0 to 100% EtOAc/hexanes toproduce tert-butyl4-((4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate(XLV) as a white solid (3.56 g, 6.73 mmol, 81.3% yield). ESIMS found forC₂₉H₃₂N₆O₄ m/z 529.3 (M+H).

Step 3

To a solution of tert-butyl4-((4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)oxy)piperidine-1-carboxylate(XLV) (5.56 g, 6.73 mmol) in MeOH (67.4 mL) was added HCl in dioxane(16.8 mL, 67.35 mmol). The reaction was stirred at 60° C. for 4 h. Thesolvent was neutralized by 7 N NH₃ in MeOH and then removed under vacuumand the residue was purified by silica gel (120 g) using 0 to 10% 1.0 NNH₃ in MeOH/CHCl₃ to produceN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide(16) as a white solid (2.51 g, 5.56 mmol, 82.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.48-1.58 (m, 2H), 1.92-2.00 (m, 2H), 2.56-2.65 (m, 2H),2.98 (dt, J=12.49, 3.91 Hz, 2H), 3.91 (s, 3H), 5.06-5.15 (m, 1H), 7.34(s, 1H), 7.50 (dd, J=5.21, 1.37 Hz, 1H), 7.82 (dd, J=8.51, 1.37 Hz, 1H),8.06 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.31 (d, J=5.21 Hz,1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.12 (s, 1H), 11.06 (br s, 1H); ESIMSfound for C₂₄H₂₄N₆O₂ m/z 429.2 (M+1).

Step 4

To a solution ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide(16) (1.1 g, 2.57 mmol) in MeOH (25.7 mL) was added formaldehyde (275.2mg, 3.35 mmol), HOAc (464 mg, 7.72 mmol) and NaBH(OAc)₃ (818 mg, 3.86mmol). The reaction was stirred at room temperature for 16 h. Thesolvent was removed under vacuum and the residue was purified by silicagel (40 g) using 0 to 30% 1.0 N NH₃ in MeOH/CHCl₃ to produceN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide (17) as an off-white solid (1.02 g, 2.20 mmol, 85.4%yield). ¹H NMR (499 MHz, DMSO-d₆) δ ppm 1.66-1.76 (m, 2H), 1.99 (br dd,J=9.47, 3.70 Hz, 2H), 2.17 (br s, 2H), 2.19 (s, 3H), 2.61-2.70 (m, 2H),3.91 (s, 3H), 5.01-5.09 (m, 1H), 7.35 (s, 1H), 7.51 (dd, J=5.21, 1.37Hz, 1H), 7.82 (dd, J=8.64, 1.51 Hz, 1H), 8.06 (d, J=8.78 Hz, 1H), 8.11(s, 1H), 8.15 (s, 1H), 8.31 (d, J=5.21 Hz, 1H), 8.38 (s, 1H), 8.57 (s,1H), 9.12 (s, 1H), 11.06 (s, 1H); ESIMS found for C₂₅H₂₆N₆O₂ m/z 443.2(M+1).

Example 4 Preparation ofN-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide(84) and 1′-methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide(85) are Depicted Below in Scheme 17

Step 1

In a sealed tube containing1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine(XLVII) (0.29 g, 1.32 mmol), K₃PO₄ (2.2 mL, 2.2 mmol) Pd(dppf)Cl₂—CH₂Cl₂adduct (180 mg, 0.220 mmol) in 1,4-Dioxane (8 mL) was added2-iodo-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(XLVI) (0.4 g, 0.880 mmol). This mixture was degassed with Ar sealed andheated to 70° C. for 16 h. The solvent was removed and the residue waspurified by silica gel, (0-10% 1.5 N NH₃ in MeOH/CHCl₃) to produce2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(85) (247 mg, 0.582 mmol, 66.2% yield) as an off-white solid. ESIMSfound for C₂₅H₂₇BrN₄O₄ m/z 426.1 (M+H). ¹H NMR (499 MHz, DMSO-d₆) δ ppm2.31 (3H, s), 2.57-2.63 (2H, m), 2.63-2.70 (2H, m), 3.11 (2H, br d,J=3.02 Hz), 3.91 (3H, s), 6.89 (1H, t, J=3.43 Hz), 7.78 (1H, dd, J=4.94,1.37 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.08 (1H, d, J=8.51 Hz), 8.11(1H, s), 8.16 (2H, d, J=6.04 Hz), 8.38 (1H, s), 8.61 (1H, s), 8.71 (1H,d, J=4.94 Hz), 9.14 (1H, s), 11.23 (1H, s); ESIMS found for C₂₅H₂₄N₆Om/z 425.0 (M+1).

Step 2

To a solution of2-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(85) (200 mg, 0.470 mmol) to EtOH (15 mL), degassed solvent with N₂,added palladium on carbon (100.3 mg, 0.050 mmol) and stirred thereaction over H₂ for 16 h. The reaction was filtered through Celite, thesolvent was removed under vacuum and the residue was purified by silcaGel (24 g) (0→10% 1.5 N NH₃ in CHCl₃) to produce2-(1-methyl-4-piperidyl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(84) (100 mg, 0.235 mmol, 49.8% yield) as an off-white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 1.77-1.92 (4H, m), 2.00 (2H, td, J=11.60, 2.61Hz), 2.21 (3H, s), 2.72 (1H, tt, J=11.49, 4.15 Hz), 2.85-2.93 (2H, m),3.91 (3H, s), 7.76 (1H, dd, J=5.21, 1.65 Hz), 7.82 (1H, dd, J=8.51, 1.65Hz), 7.91 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.12 (1H, d, J=0.82 Hz),8.15 (1H, d, J=0.82 Hz), 8.39 (1H, s), 8.60 (1H, s), 8.66-8.71 (1H, m),9.13 (1H, s), 11.17 (1H, s); ESIMS found for C₂₅H₂₆N₆O m/z 427.0 (M+1).

Example 5 Preparation ofN-(6-(1-methyl-5-(morpholinomethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide (204) andN-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide(429) are Depicted Below in Scheme 18

Steps 1-2

To a mixture of 6-bromoisoquinolin-3-amine (XX) (4.0 g, 17.93 mmol),Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.03 g, 1.26 mmol), KOAc (4.39 g, 44.83 mmol)and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(5.01 g, 19.72 mmol) in 1,4-dioxane (50 mL) was bubbled with N₂ for 2min. The reaction mixture was sealed and heated at 90° C. for 1.5 h. Thereaction was cooled to room temperature, filtered and washed with EtOAc.The filtrate was concentrated and the residue taken in dioxane (50 mL).To the suspension was added 4-bromo-2-methyl-pyrazole-3-carbaldehyde(XLVIII) (3.39 g, 17.93 mmol) followed by K₃PO₄ (9.52 g, 44.83 mmol),Pd(dppf)Cl₂—CH₂Cl₂ adduct (1.03 g, 1.26 mmol) and water (15 mL). Themixture was purged with N₂ for a min, sealed and heated again at 90° C.for 19 h. The mixture was cooled to room temperature and concentrated toabout 20 mL. The concentrate was diluted with EtOAc and filtered througha pad of Celite. The filtrate was diluted with water and the organiclayer separated. The organic layer was washed with brine; dried,filtered and concentrated. The residue was triturated in ether and theresulting solid filtered to afford4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (XLIX) (4.1g, 16.2 mmol, 90.6% yield) as a brown solid. ¹H NMR (499 MHz, DMSO-d₆) δppm 0.01 (6H, s), 0.86 (9H, s), 0.88-1.00 (2H, m), 1.23-1.35 (2H, m),1.35-1.46 (1H, m), 1.69-1.79 (2H, m), 1.85-1.95 (2H, m), 2.21 (1H, tt,J=12.21, 3.57 Hz), 3.38 (2H, d, J=6.31 Hz), 3.57 (3H, s)ESIMS found forC₁₄H₁₂N₄O m/z 252.95 (M+1).

Step 3

To a mixture of4-(3-amino-6-isoquinolyl)-2-methyl-pyrazole-3-carbaldehyde (XLIX) (1.07g, 4.25 mmol), piperidine (0.84 mL, 8.51 mmol) and catalytic HOAc in DCE(10 mL) was stirred for 30 min. Na(OAc)₃BH (1.8 g, 8.51 mmol) was addedand stirring was continued for 12 h at room temperature. The reactionmixture was quenched with minimum amount of aq. saturated ammoniumchloride solution, and concentrated under vacuum. The residue wasadsorbed on silica gel and purified by chromatography (0→20% 7NNH₃-MeOH/CHCl₃) to obtain6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine (L)(800 mg, 2.49 mmol, 58.5% yield) as a white solid. ESIMS found forC₁₉H₂₃N₅ m/z 322.2 (M+1).

Step 4

To a suspension of6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]isoquinolin-3-amine (L)(0.14 g, 0.440 mmol), 2-fluoropyridine-4-carboxylic acid (LI) (0.07 g,0.520 mmol), DMAP (0.03 g, 0.220 mmol) and HATU (0.2 g, 0.520 mmol) inDMF (4 mL) was added DIPEA (0.23 mL, 1.31 mmol). The resulting mixturewas stirred at 80° C. for 1.5 h. Another 1.2 equiv. of HATU was added tothe mixture and stirred at 80° C. for additional 16 h. The reactionmixture was diluted with water and the resulting solid filtered. Thecrude product was purified by silica gel chromatography (0→10% 7 NNH₃-MeOH/CHCl₃) to produce2-fluoro-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]pyridine-4-carboxamide(LII) (85.0 mg, 0.191 mmol, 43.9% yield) as a brown solid. ESIMS foundfor C₂₅H₂₅FN₆O m/z 444.9 (M+H).

Step 5

To a solution of2-fluoro-N-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]pyridine-4-carboxamide(LII) (80 mg, 0.180 mmol) in DMSO (1 mL) was added morpholine (0.05 mL,0.540 mmol). The mixture was sealed in a tube and irradiated with MW at120° C. for 30 min. The reaction was heated at 90° C. for additional 16h and the mixture cooled to room temperature, poured into water and theresulting solid filtered. The crude product was purified by silica gelchromatography (0→5% MeOH/CHCl₃) as the eluent, followed by HPLCpurification (0→65% MeCN/water). Two clean products were separated. Thefractions for each product were combined and concentrated. The residuefor each product was redissolved in minimum amount of CHCl₃/MeOH andfiltered through the carbonate resin (loading: 0.23 mmol/500 mg). Thefiltrate was concentrated and the residue triturated in ether. Theresulting solid was filtered to affordN-[6-[1-methyl-5-(1-piperidylmethyl)pyrazol-4-yl]-3-isoquinolyl]-2-morprpholino-pyridine-4-carboxamide(429) (23 mg, 0.045 mmol, 25.0% yield) as a white solid; ¹H NMR (499MHz, DMSO-d₆) δ ppm 1.32-1.44 (2H, m), 1.45-1.55 (4H, m), 2.38 (4H, brs), 3.53-3.62 (4H, m), 3.67 (2H, s), 3.71-3.77 (4H, m), 3.92 (3H, s),7.21 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.76 (1H, dd, J=8.51, 1.65Hz), 7.82 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.14 (1H, s), 8.29 (1H, d,J=5.21 Hz), 8.61 (1H, s), 9.17 (1H, s), 11.01 (1H, s); ESIMS found forC₂₉H₃₃N₇O₂ m/z 512.0 (M+1) andN-[6-[1-methyl-5-(morpholinomethyl)pyrazol-4-yl]-3-isoquinolyl]-2-morpholino-pyridine-4-carboxamide(204) (10 mg, 0.020 mmol, 10.8% yield) as an off white solid. ¹H NMR(499 MHz, DMSO-d₆) δ ppm 2.42 (4H, br d, J=3.84 Hz), 3.53-3.61 (8H, m),3.70-3.78 (6H, m), 3.94 (3H, s), 7.21 (1H, dd, J=5.21, 1.37 Hz), 7.47(1H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz), 7.83 (1H, s), 8.11 (2H, d,J=11.25 Hz), 8.29 (1H, d, J=4.94 Hz), 8.62 (1H, s), 9.18 (1H, s), 11.02(1H, s); ESIMS found for C₂₈H₃₁N₇O₃ m/z 514.0 (M+1).

Example 6 Preparation ofN-(6-(5-(dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide(428) and N-(6-(5-amino-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide (430) areDepicted Below in Scheme 19

Step 1

To a solution of N-(6-bromo-3-isoquinolyl)-2-(4-methylpiperazin-1-yl)pyridine-4-carboxamide (LIII) (328 mg, 0.770 mmol) in MeOH (4 mL) wasadded molybdenum hexacorbonyl (557 mg, 2.02 mmol), Pd(dppf)Cl₂—CH₂Cl₂adduct (125.7 mg, 0.150 mmol) sonicated for a while and stirred at 75°C. for overnight. The reaction was diluted with water, extracted intoEtOAc, and purified on a silica gel column (0→100% (20% NH₃ inMeOH—CHCl₃/CHCl₃)) to yield methyl3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylate(LIV) (232 mg, 0.572 mmol, 74.4% yield). ESIMS found for C₂₂H₂₃N₈OO₃ m/z406.2 (M+H).

Step 2

To a solution of methyl3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylate(LIV) (232 mg, 0.570 mmol) in THF (4 mL) was added MeOH (4 mL) and LiOH(137 mg, 5.72 mmol) in water (3 mL). The reaction was stirred for 3 h atroom temperature. The solvent was removed and the residue was suspendedin water. Aqueous HCl was added until pH=6 and the solid was collectedby filtration to produce3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylicacid (LV) (162 mg, 0.414 mmol, 72.3% yield) as a yellow solid. ESIMSfound for C₂₁H₂₁N₅O₃ m/z 392.0 (M+H).

Step 3

A solution of3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylicacid (LV) (45 mg, 0.110 mmol), 3-amino-1,1-dimethyl-thiourea (LVI) (20.6mg, 0.170 mmol) in POCl₃ (2.25 mL, 24.14 mmol) was heated at 80° C. for60 h. The reaction was concentrated and quenched with ice and had the pHadjusted to >12 using 1N NaOH. The solid was collected by filtration toobtainN-[6-[5-(dimethylamino)-1,3,4-thiadiazol-2-yl]-3-isoquinolyl]-2-(4-methylpiperazin-1-yl)pyridine-4-carboxamide(428) (14.6 mg, 0.031 mmol, 26.8% yield) as a yellow solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 2.32 (3H, br s), 2.52-2.67 (4H, m), 3.19 (6H, s),3.64 (4H, br s), 7.14-7.21 (1H, m), 7.48 (1H, s), 8.07 (1H, dd, J=8.51,1.65 Hz), 8.17 (1H, s), 8.24-8.29 (2H, m), 8.70 (1H, s), 9.24 (1H, s),11.14 (1H, s); ESIMS found for C₂₄H₂₆N₅OS m/z 475.2 (M+1).

Step 4

A solution of3-[[2-(4-methylpiperazin-1-yl)pyridine-4-carbonyl]amino]isoquinoline-6-carboxylicacid (LV) (60 mg, 0.150 mmol), aminothiourea (LVII) (21.0 mg, 0.230mmol) in POCl₃ (3 mL, 32.19 mmol) was heated at 80° C. for 60 h. Thereaction was concentrated and quenched with ice and had the pH adjustedto >12 using 1N NaOH. The solid was collected by filtration and purifiedby column chromatography (0→100% (10% NH₃ MeOH in EtOAc/Hexanes)) toyieldN-[6-(5-amino-1,3,4-thiadiazol-2-yl)-3-isoquinolyl]-2-(4-methylpiperazin-1-yl)pyridine-4-carboxamide(430) (3.7 mg, 0.008 mmol, 5.4% yield) as a yellow solid. ¹H NMR (499MHz, DMSO-d₆) δ ppm 2.27 (3H, br s), 3.62 (4H, br s), 7.12-7.20 (1H, m),7.48 (1H, s), 7.60 (2H, s), 8.07 (1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d,J=8.78 Hz), 8.25 (1H, s), 8.27 (1H, d, J=4.94 Hz), 8.71 (1H, s), 9.24(1H, s), 11.13 (1H, s); ESIMS found for C₂₂H₂₂N₅OS m/z 447.2 (M+1).

Example 7 Preparation of1-methyl-4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine1-oxide (87) is Depicted Below in Scheme 20

Step 1

To a suspension2-(4-methylpiperazin-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(10) (109 mg, 0.250 mmol) in DCM (5 mL) was added3-chlorobenzenecarboperoxoic acid (66 mg, 0.380 mmol). The mixture wasstirred at room temperature for 2 h and concentrated. The crude productwas purified by silica gel chromatography (0→10% 7 N NH₃-MeOH/CHCl₃).The fractions containing the product were concentrated and the residuetriturated in ether. The resulting solid was filtered and dried toafford2-(4-methyl-4-oxido-piperazin-4-ium-1-yl)-N-[6-(1-methylpyrazol-4-yl)-3-isoquinolyl]pyridine-4-carboxamide(87) (65 mg, 0.147 mmol, 57.5% yield) as a white solid. ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.99 (2H, br d, J=10.70 Hz), 3.11 (3H, s), 3.41 (2H, td,J=11.53, 3.29 Hz), 3.61-3.72 (2H, m), 3.91 (3H, s), 4.25 (2H, br d,J=13.17 Hz), 7.20 (1H, dd, J=5.08, 1.23 Hz), 7.55 (1H, s), 7.82 (1H, dd,J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s),8.29 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.60 (1H, s), 9.13 (1H, s), 11.10(1H, s); ESIMS found for C₂₄H₂₅N₇O₂ m/z 444.2 (M+1).

The following compounds were prepared in accordance with the proceduredescribed in the above Examples 1-7.

N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 1

Off-white solid (38.0 mg, 0.091 mmol, 39.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (s, 3H), 2.43 (brt, J=4.80 Hz, 4H), 3.57-3.65 (m,4H), 7.16 (dd, J=5.21, 0.82 Hz, 1H), 7.46 (s, 1H), 7.88 (dd, J=8.64,1.51 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.14-8.31 (m, 1H), 8.19 (s, 1H),8.26 (d, J=5.21 Hz, 1H), 8.38-8.51 (m, 1H), 8.60 (s, 1H), 9.13 (s, 1H),11.04 (s, 1H), 13.12 (br s, 1H); ESIMS found for C₂₃H₂₃N₇O m/z 414.2(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperazin-1-yl)benzamide 2

Off-white solid (58.3 mg, 0.141 mmol, 49.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.94 (br d, J=3.29 Hz, 4H), 3.22 (br d, J=3.84 Hz, 4H),3.91 (s, 3H), 7.15 (dd, J=8.23, 1.92 Hz, 1H), 7.35 (t, J=7.96 Hz, 1H),7.48 (d, J=7.41 Hz, 1H), 7.63 (s, 1H), 7.79 (dd, J=8.51, 1.65 Hz, 1H),8.06 (d, J=8.78 Hz, 1H), 8.10-8.14 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H),9.11 (s, 1H), 10.80 (s, 1H); ESIMS found for C₂₄H₂₄N₆O m/z 413.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide3

White solid (860 mg, 1.92 mmol, 69.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (s, 3H), 2.48 (br d, J=4.94 Hz, 4H), 3.22-3.28 (m, 4H), 3.91(s, 3H), 7.15 (dd, J=8.23, 2.20 Hz, 1H), 7.35 (t, J=7.82 Hz, 1H), 7.46(d, J=7.68 Hz, 1H), 7.64 (s, 1H), 7.79 (dd, J=8.51, 1.65 Hz, 1H), 8.05(d, J=8.51 Hz, 1H), 8.09-8.14 (m, 2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11(s, 1H), 10.80 (s, 1H); ESIMS found for C₂₅H₂₆N₆O m/z 427. (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide 4

Light yellow solid (75.5 mg, 0.183 mmol, 41.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.70-1.76 (m, 4H), 2.49 (br s, 4H), 3.68 (s, 2H), 3.91(s, 3H), 7.43-7.50 (m, 1H), 7.52-7.57 (m, 1H), 7.80 (dd, J=8.51, 1.65Hz, 1H), 7.95 (d, J=7.68 Hz, 1H), 8.00 (s, 1H), 8.06 (d, J=8.51 Hz, 1H),8.11 (s, 1H), 8.13 (s, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H),10.80 (s, 1H); ESIMS found for C₂₅H₂₅N₅O m/z 412.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperidin-4-yloxy)benzamide 5

Off-white solid (540.6 mg, 1.20 mmol, 81.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.42-1.54 (m, 2H), 1.92-1.99 (m, 2H), 2.56-2.64 (m, 2H),2.97 (dt, J=12.62, 4.25 Hz, 2H), 3.91 (s, 3H), 4.49-4.61 (m, 1H), 7.16(dd, J=8.10, 1.51 Hz, 1H), 7.41 (t, J=8.23 Hz, 1H), 7.59-7.68 (m, 2H),7.80 (dd, J=8.51, 1.65 Hz, 1H), 8.06 (d, J=8.78 Hz, 1H), 8.10-8.16 (m,2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.82 (s, 1H); ESIMSfound for C₂₅H₂₅N₅O₂ m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide6

Off-white solid (115.9 mg, 0.249 mmol, 71.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.74 (m, 2H), 1.92-2.02 (m, 2H), 2.15-2.26 (m, 2H),2.19 (s, 3H), 2.58-2.68 (m, 2H), 3.91 (s, 3H), 4.48-4.58 (m, 1H), 7.16(dd, J=7.96, 1.65 Hz, 1H), 7.42 (t, J=8.23 Hz, 1H), 7.60-7.68 (m, 2H),7.80 (dd, J=8.51, 1.37 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.08-8.16 (m,2H), 8.38 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.83 (s, 1H); ESIMSfound for C₂₆H₂₇N₅O₂ m/z 442.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 7

White solid (554 mg, 1.23 mmol, 91.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.42-1.51 (m, 2H), 1.90-1.98 (m, 2H), 2.55-2.63 (m, 2H), 2.95 (dt,J=12.69, 3.95 Hz, 2H), 3.91 (s, 3H), 4.51-4.58 (m, 1H), 7.05 (d, J=8.78Hz, 2H), 7.78 (dd, J=8.51, 1.37 Hz, 1H), 8.02-8.08 (m, 3H), 8.11 (s,1H), 8.11 (br s, 1H), 8.37 (s, 1H), 8.58 (s, 1H), 9.10 (s, 1H), 10.63(s, 1H); ESIMS found for C₂₅H₂₅N₅O₂ m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-((1-methylpiperidin-4-yl)oxy)benzamide8

White solid (82.0 mg, 0.186 mmol, 89.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.72 (m, 2H), 1.91-2.02 (m, 2H), 2.14-2.26 (m, 2H),2.18 (s, 3H), 2.58-2.68 (m, 2H), 3.91 (s, 3H), 4.51 (tt, J=8.16, 3.91Hz, 1H), 7.06 (d, J=8.78 Hz, 2H), 7.78 (dd, J=8.64, 1.51 Hz, 1H),8.01-8.07 (m, 3H), 8.09-8.13 (m, 2H), 8.37 (s, 1H), 8.58 (s, 1H), 9.10(s, 1H), 10.64 (s, 1H); ESIMS found for C₂₆H₂₇N₅O₂ m/z 442.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperazin-1-yl)isonicotinamide 9

Off-white solid (57.3 mg, 0.139 mmol, 91.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.78-2.85 (m, 4H), 3.50-3.56 (m, 4H), 3.91 (s, 3H), 7.14(dd, J=5.08, 1.24 Hz, 1H), 7.42 (s, 1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H),8.07 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.25 (d, J=4.94 Hz,1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.03 (s, 1H); ESIMSfound for C₂₃H₂₃N₇O m/z 414.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide10

Tan solid (71.6 mg, 0.168 mmol, 66.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (s, 3H), 2.43 (br t, J=4.80 Hz, 4H), 3.56-3.65 (m, 4H), 3.91(s, 3H), 7.16 (dd, J=5.08, 0.96 Hz, 1H), 7.46 (s, 1H), 7.81 (dd, J=8.37,1.51 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.10-8.16 (m, 2H), 8.26 (d,J=5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.05 (s, 1H);ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide11

White solid (58.7 mg, 0.129 mmol, 88.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.01 (d, J=6.59 Hz, 6H), 2.53-2.59 (m, 4H), 2.65-2.76 (m,1H), 3.56-3.62 (m, 4H), 3.91 (s, 3H), 7.15 (d, J=5.21 Hz, 1H), 7.44 (s,1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.11 (s,1H), 8.14 (s, 1H), 8.25 (d, J=5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H),9.12 (s, 1H), 11.04 (s, 1H); ESIMS found for C₂₆H₂₉N₇O m/z 456.2 (M+1).

2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 12

Off-white solid (124.0 mg, 0.273 mmol, 68.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.38 (br d, J=2.74 Hz, 2H), 0.46 (br d, J=4.67 Hz, 2H),1.66 (dt, J=6.24, 3.05 Hz, 1H), 2.61-2.67 (m, 4H), 3.57 (br s, 4H), 3.91(s, 3H), 7.15 (d, J=4.94 Hz, 1H), 7.46 (s, 1H), 7.81 (d, J=8.23 Hz, 1H),8.07 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.25 (d, J=4.94 Hz,1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.04 (s, 1H); ESIMSfound for C₂₆H₂₇N₇O m/z 454.2 (M+1).

2-(4-(2-Fluoroethyl)piperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 13

White solid (13.2 mg, 0.029 mmol, 17.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.55-2.61 (m, 4H), 2.69 (dt, J=28.85, 4.95 Hz, 2H),3.59-3.64 (m, 4H), 4.59 (dt, J=47.85, 4.95 Hz, 2H), 7.16 (dd, J=5.08,0.96 Hz, 1H), 7.47 (s, 1H), 7.81 (dd, J=8.51, 1.37 Hz, 1H), 8.07 (d,J=8.51 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.26 (d, J=4.94 Hz, 1H),8.38 (s, 1H), 8.59 (s, 1H), 9.13 (s, 1H), 11.04 (s, 1H); ESIMS found forC₂₅H₂₆FN₇O m/z 460.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide14

Beige solid (28.0 mg, 0.062 mmol, 66.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.22 (s, 3H), 2.40 (t, J=5.08 Hz, 4H), 3.60-3.67 (m, 4H),3.91 (s, 3H), 6.90 (d, J=9.06 Hz, 1H), 7.78 (dd, J=8.51, 1.65 Hz, 1H),8.04 (d, J=8.78 Hz, 1H), 8.08-8.12 (m, 2H), 8.19 (dd, J=9.06, 2.47 Hz,1H), 8.37 (s, 1H), 8.57 (s, 1H), 8.84 (d, J=2.20 Hz, 1H), 9.09 (s, 1H),10.63 (s, 1H); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-(piperidin-4-yloxy)nicotinamide 15

White solid (29.0 mg, 0.064 mmol, 75.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.45-1.55 (m, 2H), 1.95-2.01 (m, 2H), 2.57-2.65 (m, 2H),2.98 (dt, J=12.83, 4.15 Hz, 2H), 3.91 (s, 3H), 4.60-4.69 (m, 1H), 7.82(dd, J=8.51, 1.37 Hz, 1H), 7.98-8.02 (m, 1H), 8.07 (d, J=8.51 Hz, 1H),8.11 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.45 (d, J=2.74 Hz, 1H), 8.60(s, 1H), 8.75 (d, J=1.65 Hz, 1H), 9.13 (s, 1H), 11.11 (br s, 1H); ESIMSfound for C₂₄H₂₄N₆O₂ m/z 429.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-yloxy)isonicotinamide 16

Off-white solid (113.3 mg, 0.264 mmol, 58.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.47-1.61 (2H, m), 1.92-2.01 (2H, m), 2.57-2.67 (2H, m),2.98 (2H, dt, J=12.49, 3.91 Hz), 3.91 (3H, s), 5.06-5.15 (1H, m), 7.34(1H, s), 7.50 (1H, dd, J=5.21, 1.37 Hz), 7.82 (1H, dd, J=8.51, 1.37 Hz),8.06 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.31 (1H, d, J=5.21Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 11.06 (1H, br s); ESIMSfound for C₂₄H₂₄N₆O₂ m/z 429.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)oxy)isonicotinamide17

Off-white solid (1.02 g, 2.20 mmol, 85.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.64-1.77 (2H, m), 1.99 (2H, br dd, J=8.92, 3.98 Hz),2.17 (2H, br s), 2.19 (3H, s), 2.60-2.70 (2H, m), 3.91 (3H, s), 5.04(1H, tt, J=8.40, 3.95 Hz), 7.35 (1H, s), 7.51 (1H, dd, J=5.21, 1.37 Hz),7.82 (1H, dd, J=8.51, 1.65 Hz), 8.06 (1H, d, J=8.78 Hz), 8.11 (1H, s),8.15 (1H, s), 8.31 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.57 (1H, s), 9.12(1H, s), 11.06 (1H, s); ESIMS found for C₂₅H₂₆N₆O₂ m/z 443.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-(piperidin-4-ylamino)nicotinamide 18

Off-white solid (274.3 mg, 0.610 mmol, 65.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.22-1.36 (m, 3H), 1.86 (br d, J=9.88 Hz, 2H), 2.52-2.60(m, 2H), 2.92-3.01 (m, 2H), 3.73-3.84 (m, 1H), 3.91 (s, 3H), 6.70 (d,J=7.68 Hz, 1H), 6.98 (s, 1H), 6.99-7.04 (m, 1H), 7.81 (dd, J=8.51, 1.37Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.09 (d, J=5.21 Hz, 1H), 8.11 (s, 1H),8.14 (s, 1H), 8.38 (s, 1H), 8.55 (s, 1H), 9.11 (s, 1H), 10.78 (br s,1H); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-5-((1-methylpiperidin-4-yl)amino)nicotinamide19

Off-white solid (42.3 mg, 0.091 mmol, 51.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.41-1.53 (m, 2H), 1.84-1.93 (m, 2H), 2.00 (br t, J=10.84Hz, 2H), 2.17 (s, 3H), 2.73 (br d, J=11.80 Hz, 2H), 3.65-3.76 (m, 1H),3.91 (s, 3H), 6.69 (d, J=7.41 Hz, 1H), 6.99 (s, 1H), 7.01 (dd, J=5.35,1.51 Hz, 1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H),8.09 (d, J=5.21 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.38 (s, 1H), 8.55(s, 1H), 9.11 (s, 1H), 10.79 (s, 1H); ESIMS found for C₂₅H₂₇N₇O m/z442.2 (M+1).

N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(piperidin-4-yloxy)benzamide 20

White solid (77.3 mg, 0.170 mmol, 77.3% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.44-1.54 (m, 2H), 1.49 (d, J=6.59 Hz, 6H), 1.92-2.01 (m,2H), 2.61 (ddd, J=12.49, 10.02, 2.74 Hz, 2H), 2.98 (dt, J=12.69, 4.22Hz, 2H), 4.50-4.60 (m, 2H), 7.13-7.19 (m, 1H), 7.41 (t, J=8.10 Hz, 1H),7.61-7.65 (m, 2H), 7.83 (dd, J=8.51, 1.65 Hz, 1H), 8.05 (d, J=8.51 Hz,1H), 8.11 (s, 1H), 8.15 (s, 1H), 8.48 (s, 1H), 8.59 (s, 1H), 9.11 (s,1H), 10.80 (s, 1H); ESIMS found for C₂₇H₂₉N₅O₂ m/z 456.2 (M+1).

N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide21

Off-white solid (54.6 mg, 0.116 mmol, 92.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.49 (d, J=6.59 Hz, 6H), 1.63-1.74 (m, 2H), 1.93-2.02 (m,2H), 2.16-2.26 (m, 2H), 2.19 (s, 3H), 2.58-2.68 (m, 2H), 4.50-4.59 (m,2H), 7.13-7.21 (m, 1H), 7.42 (t, J=8.23 Hz, 1H), 7.61-7.67 (m, 2H), 7.83(dd, J=8.51, 1.65 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.16(s, 1H), 8.49 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.81 (s, 1H); ESIMSfound for C₂₈H₃₁N₅O₂ m/z 470.3 (M+1).

N-(6-(1-Isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 22

White solid (52.0 mg, 0.108 mmol, 75.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.42-1.54 (m, 2H), 1.48 (d, J=6.59 Hz, 6H), 1.91-1.99 (m,2H), 2.55-2.64 (m, 2H), 2.95 (dt, J=12.83, 4.15 Hz, 2H), 4.50-4.59 (m,2H), 7.05 (d, J=8.78 Hz, 2H), 7.82 (dd, J=8.51, 1.37 Hz, 1H), 8.02-8.08(m, 3H), 8.11 (s, 1H), 8.14 (s, 1H), 8.48 (s, 1H), 8.58 (s, 1H), 9.09(s, 1H), 10.62 (s, 1H); ESIMS found for C₂₇H₂₉N₅O₂ m/z 456.2 (M+1).

N-(6-(1-Cyclopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide23

Off-white solid (83.0 mg, 0.183 mmol, 78.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.99-1.04 (m, 2H), 1.09-1.14 (m, 2H), 2.24 (s, 3H), 2.43(br t, J=4.94 Hz, 4H), 3.58-3.65 (m, 4H), 3.79 (tt, J=7.38, 3.88 Hz,1H), 7.12-7.19 (m, 1H), 7.46 (s, 1H), 7.84 (dd, J=8.64, 1.51 Hz, 1H),8.06 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.16 (s, 1H), 8.26 (d, J=4.94 Hz,1H), 8.49 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.04 (s, 1H); ESIMSfound for C₂₆H₂₇N₇O m/z 454.2 (M+1).

4-Fluoro-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 24

Beige solid (49.0 mg, 0.108 mmol, 53.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.94-2.13 (m, 6H), 2.22 (s, 3H), 2.88 (br d, J=11.25 Hz,2H), 4.11-4.21 (m, 1H), 7.36 (t, J=8.92 Hz, 2H), 7.83 (dd, J=8.51, 1.37Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.12-8.20 (m, 4H), 8.51 (s, 1H), 8.59(s, 1H), 9.11 (s, 1H), 10.89 (s, 1H); ESIMS found for C₂₅H₂₄FN₅O m/z430.2 (M+1).

4-(Difluoromethoxy)-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 25

Beige solid (67.0 mg, 0.133 mmol, 52.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.95-2.11 (m, 6H), 2.22 (s, 3H), 2.88 (br d, J=10.98 Hz,2H), 4.11-4.20 (m, 1H), 7.40 (t, J=73.95 Hz, 1H), 7.31 (d, J=8.78 Hz,2H), 7.83 (dd, J=8.51, 1.37 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.13 (s,1H), 8.15-8.18 (m, 3H), 8.51 (s, 1H), 8.59 (s, 1H), 9.11 (s, 1H), 10.88(s, 1H); ESIMS found for C₂₆H₂₅F₂N₅O₂ m/z 478.2 (M+1).

5-Fluoro-N-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)nicotinamide 26

White solid (38.0 mg, 0.088 mmol, 75.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.95-2.11 (m, 6H), 2.22 (s, 3H), 2.88 (br d, J=11.25 Hz,2H), 4.11-4.20 (m, 1H), 7.86 (dd, J=8.78, 1.37 Hz, 1H), 8.07 (d, J=8.51Hz, 1H), 8.14 (s, 1H), 8.19 (s, 1H), 8.33 (dt, J=9.47, 2.26 Hz, 1H),8.52 (s, 1H), 8.60 (s, 1H), 8.80 (d, J=2.74 Hz, 1H), 9.07 (s, 1H), 9.13(s, 1H), 11.24 (s, 1H); ESIMS found for C₂₄H₂₃FN₆O m/z 431.2 (M+1).

N²-Methyl-N⁵-(6-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)pyridine-2,5-dicarboxamide27

Beige solid (23.0 mg, 0.049 mmol, 31.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.96-2.12 (m, 6H), 2.22 (s, 3H), 2.89 (br s, 2H), 2.85(d, J=4.67 Hz, 3H), 4.12-4.20 (m, 1H), 7.86 (dd, J=8.51, 1.65 Hz, 1H),8.07 (d, J=8.51 Hz, 1H), 8.13-8.17 (m, 2H), 8.19 (s, 1H), 8.52 (s, 1H),8.55 (dd, J=7.96, 2.20 Hz, 1H), 8.62 (s, 1H), 8.94 (q, J=4.85 Hz, 1H),9.13 (s, 1H), 9.21 (d, J=1.92 Hz, 1H), 11.30 (s, 1H); ESIMS found forC₂₆H₂₇N₇O₂ m/z 470.2 (M+1).

4-Fluoro-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 28

Beige solid (43.0 mg, 0.122 mmol, 46.7% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 3.86 (s, 3H), 7.28 (t, J=8.78 Hz, 2H), 7.45 (br s,1H), 7.68 (d, J=8.51 Hz, 1H), 7.94 (br s, 1H), 8.00 (s, 1H), 8.06-8.15(m, 3H), 8.66 (s, 1H), 9.13 (br s, 1H); ESIMS found for C₂₀H₁₅FN₄O m/z347.1 (M+1).

4-(Difluoromethoxy)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 29

White solid (16.0 mg, 0.040 mmol, 15.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 7.41 (1H, t, J=73.70 Hz), 7.31 (1H, s),7.32 (1H, s), 7.33 (1H, br s), 7.73 (1H, dd, J=8.37, 1.51 Hz), 7.81 (1H,s), 8.09 (1H, s), 8.15 (1H, d, J=8.51 Hz), 8.16-8.17 (1H, m), 8.17-8.21(1H, m), 8.69 (1H, s), 9.22 (1H, s), 10.96 (1H, s); ESIMS found forC₂₁H₁₆F₂N₄O₂ m/z 395.1 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide37

White solid (102.0 mg, 0.239 mmol, 82.9% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.38-2.46 (4H, m), 3.55-3.64 (4H, m), 3.85(3H, s), 7.16 (1H, dd, J=5.08, 1.23 Hz), 7.33 (1H, d, J=1.10 Hz), 7.48(1H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, d,J=0.82 Hz), 8.15 (1H, d, J=8.51 Hz), 8.24-8.28 (1H, m), 8.70 (1H, s),9.23 (1H, s), 11.11 (1H, s); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-isopropoxybenzamide40

Light green solid (33.0 mg, 0.082 mmol, 31.7% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.31 (d, J=6.04 Hz, 6H), 2.47 (br s, 3H), 3.71 (br s,3H), 4.75 (dquin, J=12.06, 5.97, 5.97, 5.97, 5.97 Hz, 1H), 7.03 (d,J=9.06 Hz, 2H), 7.32 (br s, 1H), 7.65 (br d, J=8.23 Hz, 1H), 8.02 (br s,1H), 8.05-8.09 (m, 2H), 8.15 (br d, J=8.51 Hz, 1H), 8.68 (br s, 1H),9.22 (br s, 1H), 10.71 (br s, 1H); ESIMS found for C₂₄H₂₄N₄O₂ m/z 401.2(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide45

White solid (30.0 mg, 0.065 mmol, 41.1% yield). ¹HNMR (499 MHz, DMSO-d₆)δ ppm 1.42-1.53 (m, 2H), 1.91-1.98 (m, 2H), 2.40 (s, 3H), 2.55-2.63 (m,2H), 2.95 (dt, J=12.62, 4.12 Hz, 2H), 3.68 (s, 3H), 4.49-4.58 (m, 1H),7.06 (d, J=8.78 Hz, 2H), 7.13 (s, 1H), 7.64 (dd, J=8.51, 1.65 Hz, 1H),7.97 (s, 1H), 8.06 (d, J=8.78 Hz, 2H), 8.12 (d, J=8.51 Hz, 1H), 8.66 (s,1H), 9.19 (s, 1H), 10.69 (s, 1H); ESIMS found for C₂₆H₂₇N₅O₂ m/z 442.1(M+1).

4-(Benzyloxy)-N-(6-(1,2-dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)benzamide 47

Beige solid (114.0 mg, 0.254 mmol, 64.8% yield). ¹¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.41 (s, 3H), 3.69 (s, 3H), 5.22 (s, 2H), 7.12-7.19 (m,3H), 7.31-7.38 (m, 1H), 7.42 (t, J=7.41 Hz, 2H), 7.48 (d, J=7.14 Hz,2H), 7.64 (dd, J=8.64, 1.51 Hz, 1H), 7.99 (s, 1H), 8.10 (d, J=8.78 Hz,2H), 8.13 (d, J=8.51 Hz, 1H), 8.67 (s, 1H), 9.20 (s, 1H), 10.73 (s, 1H);ESIMS found for C₂₈H₂₄N₄O₂ m/z 449.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide49

Beige solid (12.0 mg, 0.027 mmol, 11.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.40 (3H, s), 2.41-2.44 (4H, m), 3.53-3.64(4H, m), 3.68 (3H, s), 7.14 (1H, s), 7.16 (1H, dd, J=5.21, 1.10 Hz),7.47 (1H, s), 7.67 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, s), 8.14 (1H, d,J=8.51 Hz), 8.26 (1H, d, J=4.94 Hz), 8.67 (1H, s), 9.22 (1H, s), 11.09(1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.0 (M+1).

4-Isopropoxy-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl) benzamide 52

Beige solid (20.0 mg, 0.044 mmol, 27.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31 (d, J=6.04 Hz, 6H), 2.79 (br s, 1H), 3.08 (br t,J=5.21 Hz, 2H), 3.96 (s, 2H), 4.13 (t, J=5.21 Hz, 2H), 4.75 (spt, J=6.04Hz, 1H), 7.03 (d, J=8.78 Hz, 2H), 7.31 (s, 1H), 7.69 (dd, J=8.64, 1.51Hz, 1H), 8.01 (s, 1H), 8.07 (d, J=8.78 Hz, 2H), 8.10 (d, J=8.78 Hz, 1H),8.66 (s, 1H), 9.17 (s, 1H), 10.67 (s, 1H); ESIMS found for C₂₅H₂₅N₅O₂m/z 428.2 (M+1).

2-(4-Aminopiperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide53

Off-white solid (195.0 mg, 0.456 mmol, 81.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.19-1.29 (2H, m), 1.76-1.85 (2H, m), 2.80-2.90 (1H, m),2.93-3.04 (2H, m), 3.91 (3H, s), 4.32 (2H, br d, J=13.17 Hz), 7.10 (1H,dd, J=5.21, 1.10 Hz), 7.45 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07(1H, d, J=8.78 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.23 (1H, d, J=4.94 Hz),8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.03 (1H, br s); ESIMS foundfor C₂₄H₂₅N₇₀ m/z 428.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methylamino)piperidin-1-yl)isonicotinamide 54

White solid (69.0 mg, 0.156 mmol, 41.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.17-1.31 (m, 2H), 1.88 (br d, J=10.43 Hz, 2H), 2.31 (s,3H), 2.52-2.60 (m, 1H), 3.01 (br t, J=11.11 Hz, 2H), 3.91 (s, 3H), 4.29(br d, J=13.17 Hz, 2H), 7.10 (d, J=5.21 Hz, 1H), 7.44 (s, 1H), 7.81 (d,J=8.51 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H),8.23 (d, J=4.94 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H), 9.12 (s, 1H), 11.03(br s, 1H); ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 55

Off-white solid (30.0 mg, 0.066 mmol, 31.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.37 (2H, qd, J=11.94, 3.70 Hz), 1.83 (2H, br d, J=11.25Hz), 2.19 (6H, s), 2.30-2.40 (1H, m), 2.83-2.94 (2H, m), 3.91 (3H, s),4.44 (2H, br d, J=13.17 Hz), 7.11 (1H, dd, J=5.21, 1.10 Hz), 7.45 (1H,s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H,s), 8.13 (1H, s), 8.24 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.59 (1H, s),9.12 (1H, s), 11.03 (1H, s); ESIMS found for C₂₆H₂₉N₇O m/z 456.2 (M+1).

2-((1-Isopropylpiperidin-4-yl)oxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 56

White solid (20.0 mg, 0.043 mmol, 12.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.99 (d, J=6.31 Hz, 6H), 1.61-1.71 (m, 2H), 1.96-2.05 (m,2H), 2.28-2.39 (m, 2H), 2.68-2.79 (m, 3H), 3.91 (s, 3H), 4.98-5.07 (m,1H), 7.35 (s, 1H), 7.50 (dd, J=5.35, 1.51 Hz, 1 H), 7.82 (dd, J=8.64,1.51 Hz, 1H), 8.06 (d, J=8.51 Hz, 1H), 8.11 (d, J=0.82 Hz, 1H), 8.15 (s,1H), 8.31 (d, J=5.76 Hz, 1H), 8.38 (s, 1H), 8.57 (s, 1H), 9.12 (s, 1H),11.06 (s, 1H); ESIMS found for C₂₇H₃₀N₆O₂ m/z 471.2 (M+1).

2-(3-Aminoazetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 57

Off-white solid (200.4 mg, 0.502 mmol, 65.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.17 (br s, 2H), 3.62 (dd, J=8.10, 5.90 Hz, 2H),3.80-3.89 (m, 1H), 4.19 (t, J=7.68 Hz, 2H), 7.01 (s, 1H), 7.14 (dd,J=5.21, 1.37 Hz, 1H), 7.81 (dd, J=8.64, 1.51 Hz, 1H), 8.07 (d, J=8.51Hz, 1H), 8.11 (s, 1H), 8.13 (s, 1H), 8.19 (d, J=5.21 Hz, 1H), 8.38 (s,1H), 8.58 (s, 1H), 9.12 (s, 1H), 10.97 (s, 1H); ESIMS found forC₂₂H₂₁N₇O m/z 400.2 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 59

Off-white solid (286.7 mg, 0.671 mmol, 77.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.14 (6H, s), 3.19-3.26 (1H, m), 3.81 (2H, dd, J=8.51,5.21 Hz), 3.91 (3H, s), 4.04-4.12 (2H, m), 7.03 (1H, s), 7.15 (1H, dd,J=5.21, 1.65 Hz), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.06 (1H, d, J=8.78Hz), 8.10 (1H, d, J=0.82 Hz), 8.13 (1H, s), 8.21 (1H, d, J=5.21 Hz),8.37 (1H, s), 8.57 (1H, s), 9.12 (1H, s), 10.92 (1H, s); ESIMS found forC₂₄H₂₅N₇O m/z 428.0 (M+1).

2-Fluoro-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)benzamide60

Off-white solid (18.0 mg, 0.052 mmol, 13.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 4.15 (s, 3H), 7.32-7.39 (m, 2H), 7.55-7.65 (m, 1H), 7.76(td, J=7.55, 1.65 Hz, 1H), 8.08 (dd, J=8.51, 1.65 Hz, 1H), 8.16 (d,J=8.78 Hz, 1H), 8.39 (s, 1H), 8.64 (s, 1H), 8.75 (s, 1H), 9.17 (s, 1H),10.88 (s, 1H); ESIMS found for C₁₉H₁₄FN₅O m/z 348.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide61

Tan solid (72.9 mg, 0.176 mmol, 60.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.54-3.61 (m, 4H), 3.71-3.77 (m, 4H), 3.91 (s, 3H), 7.21 (dd,J=5.08, 1.23 Hz, 1H), 7.47 (s, 1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.07(d, J=8.78 Hz, 1H), 8.11 (s, 1H), 8.14 (s, 1H), 8.29 (d, J=5.21 Hz, 1H),8.38 (s, 1H), 8.60 (s, 1H), 9.13 (s, 1H), 11.05 (s, 1H); ESIMS found forC₂₃H₂₂N₆O₂ m/z 415.2 (M+1).

2-((2-(Dimethylamino)ethyl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 62

Tan solid (79.2 mg, 0.191 mmol, 66.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.19 (s, 6H), 2.43 (t, J=6.72 Hz, 2H), 3.35-3.43 (m, 2H), 3.91 (s,3H), 6.61 (t, J=5.49 Hz, 1H), 7.02 (dd, J=5.21, 1.37 Hz, 1H), 7.04 (s,1H), 7.81 (dd, J=8.51, 1.65 Hz, 1H), 8.06 (d, J=8.78 Hz, 1H), 8.08-8.12(m, 2H), 8.14 (s, 1H), 8.38 (s, 1H), 8.56 (s, 1H), 9.11 (s, 1H), 10.80(s, 1H); ESIMS found for C₂₃H₂₅N₇O m/z 416.2 (M+1).

2-(2-(Dimethylamino)ethoxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide63

Tan solid (84.1 mg, 0.202 mmol, 70.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.23 (s, 6H), 2.65 (t, J=5.76 Hz, 2H), 3.91 (s, 3H), 4.41 (t,J=5.90 Hz, 2H), 7.39 (d, J=0.82 Hz, 1H), 7.53 (dd, J=5.21, 1.37 Hz, 1H),7.82 (dd, J=8.51, 1.65 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.11 (s, 1H),8.15 (s, 1H), 8.33 (d, J=5.21 Hz, 1H), 8.38 (s, 1H), 8.58 (s, 1H), 9.12(s, 1H), 11.08 (s, 1H); ESIMS found for C₂₃H₂₄N₆O₂ m/z 417.2 (M+1).

2-(4-Isobutylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide64

Off-white solid (61.3 mg, 0.131 mmol, 45.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.90 (d, J=6.59 Hz, 6H), 1.83 (dquin, J=13.48, 6.85,6.85, 6.85, 6.85 Hz, 1H), 2.09 (d, J=7.41 Hz, 2H), 2.45 (br t, J=4.94Hz, 4H), 3.57-3.64 (m, 4H), 3.91 (s, 3H), 7.12-7.18 (m, 1H), 7.45 (s,1H), 7.81 (dd, J=8.51, 1.37 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.11 (s,1H), 8.14 (s, 1H), 8.25 (d, J=5.21 Hz, 1H), 8.38 (s, 1H), 8.59 (s, 1H),9.12 (s, 1H), 11.04 (s, 1H); ESIMS found for C₂₇H₃₁N₇O m/z 470.2 (M+1).

2-(Azetidin-3-yloxy)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 65

Off-white solid (64.9 mg, 0.162 mmol, 23.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.51-3.58 (m, 2H), 3.77 (br t, J=7.68 Hz, 2H), 3.91 (s,3H), 5.39 (quin, J=6.24 Hz, 1H), 7.40 (s, 1H), 7.54 (dd, J=5.21, 1.37Hz, 1H), 7.82 (dd, J=8.51, 1.37 Hz, 1H), 8.07 (d, J=8.51 Hz, 1H), 8.11(s, 1H), 8.15 (s, 1H), 8.30 (d, J=5.21 Hz, 1H), 8.38 (s, 1H), 8.58 (s,1H), 9.13 (s, 1H), 11.09 (br s, 1H); ESIMS found for C₂₂H₂₀N₆O₂ m/z401.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylazetidin-3-yl)oxy)isonicotinamide66

Off-white solid (144.0 mg, 0.347 mmol, 48.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.30 (3H, s), 2.99-3.05 (2H, m), 3.69-3.77 (2H, m), 3.91(3H, s), 5.16 (1H, quin, J=5.76 Hz), 7.40 (1H, d, J=1.37 Hz), 7.55 (1H,dd, J=5.21, 1.37 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d,J=8.78 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.30 (1H, d, J=5.49 Hz), 8.38(1H, s), 8.58 (1H, s), 9.12 (1H, s), 11.09 (1H, s); ESIMS found forC₂₃H₂₂N₆O₂ m/z 415.0 (M+1).

2-(4-Ethylpiperazin-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 67

Tan solid (98.3 mg, 0.223 mmol, 77.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.05 (3H, t, J=7.27 Hz), 2.38 (2H, q, J=7.14 Hz), 2.46-2.49 (4H,m), 3.57-3.64 (4H, m), 3.91 (3H, s), 7.16 (1H, dd, J=4.94, 1.10 Hz),7.46 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz),8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.59(1H, s), 9.12 (1H, s), 11.04 (1H, s) ESIMS found for C₂₅H₂₇N₇O m/z 442.2(M+1).

4-((Dimethylamino)methyl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide71

Off-white solid (15.2 mg, 0.039 mmol, 14.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.19 (6H, s), 3.49 (2H, s), 3.91 (3H, s), 7.44 (2H, d,J=8.23 Hz), 7.79 (1H, dd, J=8.51, 1.65 Hz), 8.05 (3H, d, J=8.23 Hz),8.10 (1H, s), 8.12 (1H, s), 8.36 (1H, s), 8.59 (1H, s), 9.11 (1H, s),10.70 (1H, s); ESIMS found for C₂₃H₂₃N₅O m/z 386.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(1-methylpiperidin-4-yl)benzamide72

Off-white solid (78.0 mg, 0.174 mmol, 75.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.72-1.84 (4H, m), 2.00 (2H, td, J=10.91, 3.16 Hz), 2.22(3H, s), 2.52-2.60 (1H, m), 2.90 (2H, br d, J=11.25 Hz), 3.91 (3H, s),7.40-7.51 (2H, m), 7.79 (1H, dd, J=8.51, 1.37 Hz), 7.89 (1H, br d,J=7.41 Hz), 8.01 (1H, s), 8.05 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.12(1H, s), 8.37 (1H, s), 8.59 (1H, s), 9.11 (1H, s), 10.80 (1H, s); ESIMSfound for C₂₆H₂₇N₅O m/z 426.05 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-((4-methylpiperazin-1-yl)methyl)benzamide74

Off-white solid (65.0 mg, 0.196 mmol, 33.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.16 (3H, s), 2.27-2.38 (4H, m), 2.38-2.45 (4H, m), 3.54(2H, s), 3.92 (3H, s), 7.44-7.50 (1H, m), 7.50-7.55 (1H, m), 7.79 (1H,dd, J=8.64, 1.51 Hz), 7.96 (1H, br d, J=7.68 Hz), 7.98 (1H, s), 8.06(1H, d, J=8.51 Hz), 8.10 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H,s), 9.11 (1H, s), 10.74 (1H, s); ESIMS found for C₂₆H₂₈N₆O m/z 441.0(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 76

Brown solid (80 mg, 0.243 mmol, 41.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.91 (3H, s), 7.84 (1H, dd, J=8.51, 1.65 Hz), 8.09 (1H, d, J=8.51Hz), 8.12 (1H, s), 8.16-8.21 (3H, m), 8.39 (1H, s), 8.60 (1H, s), 8.92(2H, d, J=6.31 Hz), 9.16 (1H, s), 11.38 (1H, s); ESIMS found forC₁₉H₁₅N₅O m/z 330.1 (M+1).

2-Hydroxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 78

Off-white solid (89.0 mg, 0.258 mmol, 21.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.91 (3H, s), 6.62 (1H, dd, J=6.72, 1.51 Hz), 6.92 (1H,d, J=1.10 Hz), 7.50 (1H, d, J=6.59 Hz), 7.81 (1H, dd, J=8.51, 1.37 Hz),8.06 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.14 (1H, s), 8.37 (1H, s), 8.53(1H, s), 9.11 (1H, s), 10.97 (1H, s), 11.81 (1H, br s); ESIMS found forC₁₉H₁₅N₅O₂ m/z 345.9 (M+1).

2-Isopropoxy-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 80

Off-white solid (49.2 mg, 0.127 mmol, 38.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.33 (6H, d, J=6.31 Hz), 3.91 (3H, s), 5.30 (1H, spt,J=6.17 Hz), 7.30 (1H, s), 7.50 (1H, dd, J=5.35, 1.51 Hz), 7.82 (1H, dd,J=8.51, 1.65 Hz), 8.06 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.15 (1H, s),8.32 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 11.05(1H, s); ESIMS found for C₂₂H₂₁N₅O₂ m/z 388.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide84

Off-white solid (100.0 mg, 0.235 mmol, 49.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.77-1.92 (4H, m), 2.00 (2H, td, J=11.60, 2.61 Hz), 2.21(3H, s), 2.72 (1H, tt, J=11.49, 4.15 Hz), 2.85-2.93 (2H, m), 3.91 (3H,s), 7.76 (1H, dd, J=5.21, 1.65 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 7.91(1H, s), 8.07 (1H, d, J=8.51 Hz), 8.12 (1H, d, J=0.82 Hz), 8.15 (1H, d,J=0.82 Hz), 8.39 (1H, s), 8.60 (1H, s), 8.66-8.71 (1H, m), 9.13 (1H, s),11.17 (1H, s); ESIMS found for C₂₅H₂₆N₆O m/z 427.0 (M+1).

1′-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide85

Off-white solid (89.0 mg, 0.210 mmol, 17.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.31 (3H, s), 2.57-2.63 (2H, m), 2.63-2.70 (2H, m), 3.11(2H, br d, J=3.02 Hz), 3.91 (3H, s), 6.89 (1H, t, J=3.43 Hz), 7.78 (1H,dd, J=4.94, 1.37 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.08 (1H, d,J=8.51 Hz), 8.11 (1H, s), 8.16 (2H, d, J=6.04 Hz), 8.38 (1H, s), 8.61(1H, s), 8.71 (1H, d, J=4.94 Hz), 9.14 (1H, s), 11.23 (1H, s); ESIMSfound for C₂₅H₂₄N₆O m/z 425.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(6-(4-methylpiperazin-1-yl)nicotinoyl)piperazin-1-yl)isonicotinamide86

Off-white solid (30.0 mg, 0.049 mmol, 89.4% yield). ¹H NMR (499 MHz,Solvent) 6 ppm 2.21 (3H, s), 2.36-2.41 (4H, m), 3.42 (2H, br s),3.49-3.56 (4H, m), 3.64 (2H, br s), 3.75 (4H, br s), 3.91 (3H, s), 6.64(1H, dd, J=5.08, 0.96 Hz), 6.82 (1H, s), 7.20 (1H, dd, J=5.21, 1.10 Hz),7.49 (1H, s), 7.81 (1H, dd, J=8.64, 1.51 Hz), 8.07 (1H, d, J=8.51 Hz),8.11 (1H, d, J=0.82 Hz), 8.14 (1H, s), 8.18 (1H, d, J=4.94 Hz), 8.29(1H, d, J=5.21 Hz), 8.38 (1H, s), 8.60 (1H, s), 9.13 (1H, s), 11.06 (1H,s); ESIMS found for C₃₄H₃₆N₁₀O₂ m/z 617.3 (M+1).

1-Methyl-4-(4-((6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)carbamoyl)pyridin-2-yl)piperazine 1-oxide 87

White solid (65.0 mg, 0.147 mmol, 57.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.99 (2H, br d, J=10.70 Hz), 3.11 (3H, s), 3.41 (2H, td,J=11.53, 3.29 Hz), 3.61-3.72 (2H, m), 3.91 (3H, s), 4.25 (2H, br d,J=13.17 Hz), 7.20 (1H, dd, J=5.08, 1.23 Hz), 7.55 (1H, s), 7.82 (1H, dd,J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s),8.29 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.60 (1H, s), 9.13 (1H, s), 11.10(1H, s); ESIMS found for C₂₄H₂₅N₇O₂ m/z 444.2 (M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)isonicotinamide88

Brown solid (33.2 mg, 0.075 mmol, 26.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.39 (3H, s), 2.40-2.44 (4H, m), 3.54-3.62(4H, m), 3.91 (3H, s), 7.04 (1H, s), 7.26 (1H, s), 7.81 (1H, dd, J=8.51,1.65 Hz), 8.06 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, d, J=0.82Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.94 (1H, s); ESIMSfound for C₂₅H₂₇N₇O m/z 442.2 (M+1).

3-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide89

Brown solid (18.8 mg, 0.043 mmol, 11.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.29 (3H, s), 2.45-2.54 (4H, m), 3.09 (4H,br s), 3.91 (3H, s), 7.08 (1H, d, J=4.94 Hz), 7.80 (1H, dd, J=8.51, 1.65Hz), 8.04 (1H, d, J=8.78 Hz), 8.11 (1H, s), 8.16 (1H, s), 8.21 (1H, d,J=4.94 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.07 (1H, s), 11.00 (1H, s);ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 90

Off-white solid (82.0 mg, 0.186 mmol, 32.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.93 (2H, quin, J=5.76 Hz), 2.27 (3H, s), 2.48 (2H, brs), 2.59-2.67 (2H, m), 3.69 (2H, t, J=6.17 Hz), 3.78-3.85 (2H, m), 3.91(3H, s), 7.05 (1H, dd, J=5.08, 0.96 Hz), 7.21 (1H, s), 7.81 (1H, dd,J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.78 Hz), 8.11 (1H, s), 8.13 (1H, s),8.20 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.02(1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

2-((2S,6R)-2,6-Dimethylmorpholino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 91

Tan solid (32.0 mg, 0.072 mmol, 31.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.20 (6H, d, J=6.04 Hz), 2.44-2.49 (2H, m), 3.60-3.70 (2H, m),3.91 (3H, s), 4.28 (2H, br dd, J=12.76, 1.51 Hz), 7.18 (1H, dd, J=5.21,1.37 Hz), 7.44 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d,J=8.78 Hz), 8.10 (1H, d, J=0.82 Hz), 8.13 (1H, s), 8.27 (1H, d, J=5.49Hz), 8.37 (1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.94 (1H, s); ESIMSfound for C₂₅H₂₆N₆O₂ m/z 443.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide 92

Off-white solid (120.0 mg, 0.265 mmol, 47.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.66 (4H, br t, J=4.94 Hz), 2.66 (4H, br s), 3.73 (4H,s), 3.91 (3H, s), 7.02 (1H, s), 7.12 (1H, dd, J=5.21, 1.37 Hz), 7.81(1H, dd, J=8.64, 1.51 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13(1H, s), 8.19 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.58 (1H, s), 9.12 (1H,s), 10.96 (1H, br s); ESIMS found for C₂₆H₂₇N₇O m/z 454.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide93

White solid (63.9 mg, 0.137 mmol, 77.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76 (4H, br t, J=5.21 Hz), 2.15 (3H, s), 2.27 (4H, brs), 3.74 (4H, s), 3.91 (3H, s), 7.03 (1H, s), 7.13 (1H, dd, J=5.21, 1.37Hz), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H,s), 8.13 (1H, s), 8.20 (1H, d, J=5.76 Hz), 8.38 (1H, s), 8.58 (1H, s),9.12 (1H, s), 10.96 (1H, s); ESIMS found for C₂₇H₂₉N₇O m/z 468.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-7-yl)isonicotinamide 94

Off-white solid (190.0 mg, 0.419 mmol, 76.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.72-1.79 (4H, m), 3.32-3.43 (4H, m), 3.54-3.60 (4H, m),3.91 (3H, s), 7.11 (1H, dd, J=5.21, 1.10 Hz), 7.46 (1H, s), 7.81 (1H,dd, J=8.64, 1.51 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13 (1H,s), 8.23 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s),11.02 (1H, br s); ESIMS found for C₂₆H₂₇N₇O m/z 454.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)isonicotinamide95

White solid (136.0 mg, 0.291 mmol, 79.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.66-1.76 (4H, m), 2.24 (3H, s), 2.97 (4H, s), 3.53-3.62(4H, m), 3.91 (3H, s), 7.10 (1H, dd, J=5.08, 1.23 Hz), 7.45 (1H, s),7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s),8.13 (1H, s), 8.23 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12(1H, s), 11.02 (1H, s); ESIMS found for C₂₇H₂₉N₇O m/z 468.0 (M+1).

2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 97

Tan solid (72.9 mg, 0.160 mmol, 55.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.50-1.62 (2H, m), 1.80 (2H, qd, J=12.08, 3.84 Hz), 1.97-2.08 (2H,m), 2.19 (3H, s), 2.86 (2H, br d, J=11.25 Hz), 2.93 (3H, s), 3.91 (3H,s), 4.49 (1H, ddt, J=11.63, 7.79, 4.01, 4.01 Hz), 7.07 (1H, dd, J=5.08,1.23 Hz), 7.18 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H, d,J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.22 (1H, d, J=5.21 Hz), 8.38(1H, s), 8.58 (1H, s), 9.12 (1H, s), 10.99 (1H, s); ESIMS found forC₂₆H₂₉N₇O m/z 456.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide99

Off-white solid (50.0 mg, 0.109 mmol, 15.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.72 (2H, m), 1.99-2.08 (2H, m), 2.12 (2H, br t,J=10.84 Hz), 2.17 (3H, s), 2.65-2.73 (2H, m), 3.78-3.88 (1H, m), 3.91(3H, s), 7.64 (1H, dd, J=5.08, 1.51 Hz), 7.79-7.85 (2H, m), 8.07 (1H, d,J=8.51 Hz), 8.11 (1H, s), 8.15 (1H, s), 8.38 (1H, s), 8.57 (1H, s),8.59-8.64 (1H, m), 9.12 (1H, s), 11.14 (1H, s); ESIMS found forC₂₅H₂₆N₆OS m/z 458.9 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide100

Tan solid (78.0 mg, 0.182 mmol, 63.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.25 (3H, s), 2.44 (4H, br t, J=4.94 Hz), 3.82-3.89 (4H, m), 3.91(3H, s), 7.30 (1H, d, J=4.67 Hz), 7.83 (1H, dd, J=8.64, 1.51 Hz), 8.08(1H, d, J=8.78 Hz), 8.12 (1H, s), 8.17 (1H, s), 8.39 (1H, s), 8.58 (1H,s), 8.69 (1H, d, J=4.67 Hz), 9.12 (1H, s), 10.36 (1H, s); ESIMS foundfor C₂₃H₂₄N₈O m/z 429.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)pyridazine-4-carboxamide101

Off-white solid (6.2 mg, 0.015 mmol, 3.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.16 (3H, br s), 2.40 (4H, br s), 3.43 (4H, br d, J=3.57Hz), 3.91 (3H, s), 7.72 (1H, s), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.04(1H, d, J=8.78 Hz), 8.10 (1H, d, J=0.82 Hz), 8.14 (1H, s), 8.36 (1H, s),8.54 (1H, brs), 9.08 (1H, s), 11.04 (1H, s), 12.68 (1H, s); ESIMS foundfor C₂₃H₂₄N₈O m/z 429.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)pyrimidine-4-carboxamide102

White solid (72.1 mg, 0.168 mmol, 39.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.25 (3H, s), 2.44 (3H, br s), 3.76 (4H, br s), 3.91 (3H,s), 7.48 (1H, d, J=0.82 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H,d, J=8.51 Hz), 8.11 (1H, s), 8.16 (1H, s), 8.38 (1H, s), 8.58 (1H, s),8.67 (1H, d, J=1.10 Hz), 9.11 (1H, s), 10.41 (1H, s); ESIMS found forC₂₃H₂₄N₈O m/z 429.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-phenylacetamide 103

Beige solid (57.0 mg, 0.167 mmol, 37.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.77 (2H, s), 3.89 (3H, s), 7.20-7.27 (1H, m), 7.33 (2H,t, J=7.68 Hz), 7.37-7.44 (2H, m), 7.75 (1H, dd, J=8.51, 1.65 Hz), 8.00(1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1H, s), 8.34 (1H, s), 8.40 (1H,s), 9.04 (1H, s), 10.75 (1H, s); ESIMS found for C₂₁H₁₈N₄O m/z 343.1(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-phenylpropanamide 104

Beige solid (67.0 mg, 0.188 mmol, 42.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.72-2.80 (2H, m), 2.92-2.96 (2H, m), 3.90 (3H, s),7.15-7.22 (1H, m), 7.26-7.32 (4H, m), 7.74 (1H, dd, J=8.51, 1.37 Hz),7.99 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, s), 8.36 (1H, s), 8.44(1H, s), 9.02 (1H, s), 10.54 (1H, s); ESIMS found for C₂₂H₂₀N₄O m/z357.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyridin-3-yl)acetamide105

Brownish orange solid (21.0 mg, 0.061 mmol, 13.7% yield). ¹H NMR (499MHz, DMSO-d₆) δ ppm 3.83 (2H, s), 3.89 (3H, s), 7.37 (1H, dd, J=7.82,4.80 Hz), 7.76 (1H, dd, J=8.51, 1.65 Hz), 7.79 (1H, dt, J=7.82, 1.85Hz), 8.01 (1H, d, J=8.51 Hz), 8.03 (1H, s), 8.07 (1 H, s), 8.34 (1H, s),8.39 (1H, s), 8.47 (1H, dd, J=4.67, 1.65 Hz), 8.57 (1H, d, J=1.65 Hz),9.05 (1H, s), 10.86 (1H, s); ESIMS found for C₂₀H₇N₈O m/z 344.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyridin-3-yl)propanamide 106

Brown solid (65.0 mg, 0.182 mmol, 40.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.76-2.83 (2H, m), 2.93-3.00 (2H, m), 3.90 (3H, s), 7.31(1H, dd, J=7.82, 4.80 Hz), 7.69 (1H, dt, J=7.82, 1.85 Hz), 7.75 (1H, dd,J=8.51, 1.65 Hz), 7.99 (1H, d, J=8.51 Hz), 8.06 (1H, s), 8.09 (1H, d,J=0.82 Hz), 8.36 (1H, s), 8.40 (1H, dd, J=4.80, 1.51 Hz), 8.43 (1H, s),8.51 (1H, d, J=1.92 Hz), 9.01 (1H, s), 10.56 (1H, s); ESIMS found forC₂₁H₁₉N₅O m/z 358.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyridin-4-yl)acetamide107

Beige solid (30.0 mg, 0.087 mmol, 19.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.84 (2H, s), 3.89 (3H, s), 7.39 (2H, d, J=6.04 Hz), 7.76(1H, dd, J=8.64, 1.51 Hz), 8.01 (1H, d, J=8.51 Hz), 8.04 (1H, s), 8.07(1H, s), 8.35 (1H, s), 8.40 (1H, s), 8.49-8.55 (2H, m), 9.05 (1H, s),10.88 (1H, s); ESIMS found for C₂₀H₇N₈O m/z 344.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyridin-4-yl)propanamide 108

Beige solid (45.0 mg, 0.126 mmol, 28.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.77-2.85 (2H, m), 2.92-3.00 (2H, m), 3.90 (3H, s),7.27-7.33 (2H, m), 7.75 (1H, dd, J=8.51, 1.37 Hz), 8.00 (1H, d, J=8.78Hz), 8.06 (1H, s), 8.09 (1H, d, J=0.82 Hz), 8.35 (1H, s), 8.43 (1H, s),8.44-8.50 (2H, m), 9.02 (1H, s), 10.58 (1H, s); ESIMS found forC₂₁H₁₉N₅O m/z 358.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoindoline-5-carboxamide109

Off-white solid (120.0 mg, 0.325 mmol, 33.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.91 (3H, s), 4.14 (4H, s), 7.39 (1H, d, J=7.68 Hz), 7.79(1H, dd, J=8.51, 1.65 Hz), 7.92 (1H, dd, J=7.96, 1.37 Hz), 7.97 (1H, s),8.05 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.37 (1H, s), 8.59(1H, s), 9.10 (1H, s), 10.70 (1H, s); ESIMS found for C₂₂H₁₉N₅O m/z369.95 (M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoindoline-5-carboxamide110

Off-white solid. ¹H NMR (499 MHz, DMSO-d₆) δ ppm 2.52 (3H, s), 3.88 (4H,s), 3.91 (3H, s), 7.37 (1H, d, J=7.68 Hz), 7.79 (1H, dd, J=8.51, 1.65Hz), 7.90-7.97 (2H, m), 8.05 (1H, d, J=8.78 Hz), 8.10 (1H, d, J=0.82Hz), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9.10 (1H, s), 10.70 (1H,s); ESIMS found for C₂₃H₂₁N₅O m/z 383.95 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide111

Off-white solid (120.0 mg, 0.313 mmol, 32.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.73-2.78 (2H, m), 2.97 (2H, t, J=5.90 Hz), 3.90-3.93(2H, m), 3.91 (3H, s), 7.20 (1H, d, J=7.96 Hz), 7.75-7.85 (3H, m), 8.05(1H, d, J=8.51 Hz), 8.11 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H,s), 9.10 (1H, s), 10.63 (1H, s); ESIMS found for C₂₃H₂₁N₅O m/z 384.0(M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide112

Off-white solid (115.9 mg, 0.277 mmol, 93.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.37 (3H, s), 2.63 (2H, br t, J=5.90 Hz), 2.89 (2H, br t,J=5.76 Hz), 3.52-3.59 (2H, m), 3.91 (3H, s), 7.25 (1H, d, J=7.96 Hz),7.76-7.89 (3H, m), 8.05 (1H, d, J=8.51 Hz), 8.10 (1H, s), 8.12 (1H, s),8.37 (1H, s), 8.58 (1H, s), 9.10 (1H, s), 10.65 (1H, s); ESIMS found forC₂₄H₂₃N₅O m/z 398.0 (M+1).

2-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide113

Off-white solid (115.9 mg, 0.277 mmol, 65.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.36 (3H, s), 2.64 (2H, t, J=5.90 Hz), 2.91 (2H, br t,J=5.63 Hz), 3.55 (2H, s), 3.91 (3H, s), 7.19 (1H, d, J=7.96 Hz), 7.81(2H, ddd, J=17.36, 8.30, 1.51 Hz), 7.86 (1H, s), 8.05 (1H, d, J=8.51Hz), 8.10 (1H, s), 8.12 (1H, s), 8.37 (1H, s), 8.58 (1H, s), 9.10 (1H,s), 10.66 (1H, s); ESIMS found for C₂₄H₂₃N₅O m/z 398.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide114

Off-white solid (170.0 mg, 0.443 mmol, 31.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.78 (2H, br t, J=5.76 Hz), 2.98 (2H, t, J=5.90 Hz),3.86-3.97 (5H, m), 7.15 (1H, d, J=7.68 Hz), 7.76-7.82 (2H, m), 7.83 (1H,s), 8.05 (1H, d, J=8.78 Hz), 8.11 (1H, s), 8.12 (1H, s), 8.37 (1H, s),8.58 (1H, s), 9.10 (1H, s), 10.64 (1H, s); ESIMS found for C₂₃H₂₁N₅O m/z384.0 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-indole-5-carboxamide116

White solid (18.0 mg, 0.049 mmol, 10.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.91 (3H, s), 6.59 (1H, ddd, J=2.95, 1.99, 0.82 Hz),7.44-7.48 (1H, m), 7.49 (1H, d, J=8.51 Hz), 7.78 (1H, dd, J=8.51, 1.65Hz), 7.86 (1H, dd, J=8.64, 1.78 Hz), 8.05 (1H, d, J=8.78 Hz), 8.11 (1H,s), 8.12 (1H, d, J=0.82 Hz), 8.38 (1H, s), 8.42 (1H, d, J=1.65 Hz), 8.62(1H, s), 9.11 (1H, s), 10.53 (1H, s), 11.39 (1H, br s); ESIMS found forC₂₂H₁₇N₅O m/z 368.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzofuran-5-carboxamide117

Light yellow solid (8.7 mg, 0.024 mmol, 7.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.91 (3H, s), 7.11 (1H, d, J=1.37 Hz), 7.73 (1H, d,J=8.51 Hz), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.06 (2H, d, J=8.51 Hz),8.11 (1H, s), 8.12 (1H, d, J=2.20 Hz), 8.14 (1H, s), 8.38 (1H, s), 8.45(1H, d, J=1.92 Hz), 8.62 (1H, s), 9.12 (1H, s), 10.83 (1H, s); ESIMSfound for C₂₂H₁₆N₄O₂ m/z 369.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)furo[2,3-c]pyridine-5-carboxamide118

Light yellow solid (10.8 mg, 0.029 mmol, 9.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.30 (1H, d, J=1.92 Hz), 7.82 (1H, dd,J=8.51, 1.37 Hz), 8.07 (1H, d, J=8.51 Hz), 8.13 (1H, s), 8.18 (1H, s),8.39 (1H, s), 8.43 (1H, d, J=1.92 Hz), 8.64 (1H, s), 8.65 (1H, s), 9.12(1H, s), 9.15 (1H, s), 10.59 (1H, s); ESIMS found for C₂₁H₁₅N₅O₂ m/z370.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[b]thiophene-5-carboxamide119

Yellow solid (20.0 mg, 0.052 mmol, 14.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.61 (1H, d, J=5.49 Hz), 7.80 (1H, dd,J=8.51, 1.65 Hz), 7.90 (1H, d, J=5.49 Hz), 8.02-8.09 (2H, m), 8.12 (1H,s), 8.13-8.19 (2H, m), 8.39 (1H, s), 8.63 (1H, s), 8.66 (1H, d, J=1.10Hz), 9.13 (1H, s), 10.89 (1H, s); ESIMS found for C₂₂H₁₆N₄OS m/z 385.1(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzofuran-6-carboxamide120

Light yellow solid (6.9 mg, 0.019 mmol, 6.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.08 (1H, dd, J=2.20, 0.82 Hz), 7.80 (1H,d, J=8.23 Hz), 7.80 (1H, dd, J=8.51, 1.65 Hz), 8.01 (1H, dd, J=8.10,1.51 Hz), 8.06 (1H, d, J=8.78 Hz), 8.12 (1H, s), 8.14 (1H, s), 8.19 (1H,d, J=2.20 Hz), 8.39 (1H, s), 8.39 (1H, s), 8.62 (1H, s), 9.13 (1H, s),10.88 (1H, s); ESIMS found for C₂₂H₁₆N₄O₂ m/z 369.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]oxazole-6-carboxamide122

Yellow solid (33.4 mg, 0.090 mmol, 20.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.91 (3H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 7.94 (1H,d, J=8.51 Hz), 8.07 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.13-8.17 (2H, m),8.38 (1H, s), 8.54 (1H, d, J=1.10 Hz), 8.63 (1H, s), 8.93 (1H, s), 9.13(1H, s), 11.00 (1H, s); ESIMS found for C₂₁H₁₅N₅O₂ m/z 370.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]thiazole-6-carboxamide123

Yellow solid (35.0 mg, 0.091 mmol, 20.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H,d, J=8.51 Hz), 8.12 (1H, s), 8.16 (1H, s), 8.18-8.25 (2H, m), 8.38 (1H,s), 8.64 (1H, s), 8.91-8.96 (1H, m), 9.13 (1H, s), 9.58 (1H, s), 10.98(1H, s); ESIMS found for C₂₁H₁₅N₅OS m/z 386.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]oxazole-5-carboxamide126

Yellow solid (52.7 mg, 0.143 mmol, 32.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J=8.51, 1.37 Hz), 7.92 (1H,d, J=8.51 Hz), 8.07 (1H, d, J=8.78 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.18(1H, dd, J=8.51, 1.65 Hz), 8.38 (1H, s), 8.57 (1H, d, J=1.65 Hz), 8.62(1H, s), 8.88 (1H, s), 9.13 (1H, s), 10.99 (1H, s); ESIMS found forC₂₁H₁₅N₅O₂ m/z 370.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzo[d]thiazole-5-carboxamide127

Yellow solid (41.7 mg, 0.108 mmol, 24.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07 (1H,d, J=8.51 Hz), 8.12 (1H, d, J=0.82 Hz), 8.14-8.16 (1H, m), 8.18 (1H, dd,J=8.51, 1.65 Hz), 8.33 (1H, d, J=8.51 Hz), 8.39 (1H, s), 8.64 (1H, s),8.82 (1H, d, J=1.37 Hz), 9.14 (1H, s), 9.52 (1H, s), 11.06 (1H, s);ESIMS found for C₂₁H₁₅N₅OS m/z 386.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoline-3-carboxamide130

Beige solid (55.0 mg, 0.145 mmol, 32.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.70-7.78 (1H, m), 7.82 (1H, dd, J=8.51,1.65 Hz), 7.91 (1H, ddd, J=8.30, 6.93, 1.23 Hz), 8.08 (1H, d, J=8.51Hz), 8.10-8.14 (2H, m), 8.15 (1H, d, J=7.96 Hz), 8.17 (1H, s), 8.40 (1H,s), 8.66 (1H, s), 9.11 (1H, d, J=2.20 Hz), 9.15 (1H, s), 9.43 (1H, d,J=2.20 Hz), 11.26 (1H, s); ESIMS found for C₂₃H₁₇N₅O m/z 380.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoline-6-carboxamide131

Beige solid (57.0 mg, 0.150 mmol, 33.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.65 (1H, dd, J=8.23, 4.12 Hz), 7.82 (1H,dd, J=8.51, 1.65 Hz), 8.08 (1H, d, J=8.51 Hz), 8.10-8.16 (2H, m), 8.17(1H, s), 8.35 (1H, dd, J=8.78, 2.20 Hz), 8.39 (1H, s), 8.52-8.57 (1H,m), 8.66 (1H, s), 8.81 (1H, d, J=2.20 Hz), 9.03 (1H, dd, J=4.25, 1.78Hz), 9.15 (1H, s), 11.08 (1H, s); ESIMS found for C₂₃H₁₇N₅O m/z 380.1(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isoquinoline-6-carboxamide132

Beige solid (10.0 mg, 0.026 mmol, 5.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.92 (3H, s), 7.82 (1H, dd, J=8.51, 1.65 Hz), 7.99 (1H, d, J=5.76Hz), 8.08 (1H, d, J=8.51 Hz), 8.13 (1H, s), 8.17 (1H, s), 8.21-8.30 (2H,m), 8.39 (1H, s), 8.62 (1H, d, J=5.76 Hz), 8.65 (1H, s), 8.74 (1H, s),9.15 (1H, s), 9.44 (1H, s), 11.15 (1H, s); ESIMS found for C₂₃H₁₇N₅O m/z380.1 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)quinoxaline-6-carboxamide133

Beige solid (29.0 mg, 0.076 mmol, 17.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.08 (1H,d, J=8.51 Hz), 8.13 (1H, s), 8.17 (1H, s), 8.23 (1H, d, J=8.78 Hz), 8.39(1H, s), 8.44 (1H, dd, J=8.78, 1.92 Hz), 8.66 (1H, s), 8.84 (1H, d,J=1.92 Hz), 9.06 (1H, d, J=1.65 Hz), 9.08 (1H, d, J=1.65 Hz), 9.15 (1H,s), 11.31 (1H, s); ESIMS found for C₂₂H₁₆N₆O m/z 381.1 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide134

Off-white solid (36.0 mg, 0.081 mmol, 26.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.42 (4H, t, J=4.94 Hz), 3.55-3.65 (4H, m),3.94 (3H, s), 7.15 (1H, dd, J=5.08, 1.23 Hz), 7.46 (1H, s), 7.97 (1H, d,J=11.80 Hz), 8.14 (1H, s), 8.26 (1H, d, J=4.94 Hz), 8.33 (1H, d, J=2.74Hz), 8.37 (1H, d, J=7.41 Hz), 8.65 (1H, s), 9.14 (1H, s), 11.08 (1H, s);ESIMS found for C₂₄H₂₄FN₇O m/z 446.2 (M+1).

N-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide135

Off-white solid (65.0 mg, 0.146 mmol, 64.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.42 (4H, br t, J=4.80 Hz), 3.56-3.64 (4H,m), 3.91 (3H, s), 7.09-7.20 (1H, m), 7.46 (1H, s), 7.66 (1H, d, J=12.08Hz), 8.02 (1H, s), 8.15 (1H, s), 8.26 (1H, d, J=5.21 Hz), 8.42 (1H, s),8.65 (1H, s), 9.24 (1H, s), 11.19 (1H, s); ESIMS found for C₂₄H₂₄FN₇Om/z 446.2 (M+1).

N-(5-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide136

White solid (20.0 mg, 0.043 mmol, 41.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.26 (3H, s), 2.47 (4H, br s), 3.62 (4H, br s), 3.96 (3H,s), 7.19 (1H, dd, J=5.08, 0.96 Hz), 7.49 (1H, s), 7.84 (1H, d, J=8.51Hz), 8.08-8.12 (2H, m), 8.27 (1H, d, J=5.21 Hz), 8.48 (1H, s), 9.05 (1H,s), 9.24 (1H, s), 11.24 (1H, s); ESIMS found for C₂₄H₂₄ClN₇O m/z 462.2(M+1).

N-(7-Chloro-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide137

White solid (18.0 mg, 0.039 mmol, 37.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.27 (3H, s), 2.47 (4H, br s), 3.61 (4H, br s), 3.94 (3H,s), 7.15 (1H, dd, J=5.21, 1.10 Hz), 7.46 (1H, s), 8.01 (1H, d, J=0.82Hz), 8.20 (1H, s), 8.26 (1H, d, J=5.49 Hz), 8.32 (1H, s), 8.34 (1H, s),8.64 (1H, s), 9.18 (1H, s), 11.13 (1H, s); ESIMS found for C₂₄H₂₄ClN₇Om/z 462.2 (M+1).

N-(1-Amino-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide138

Tan solid (4.8 mg, 0.011 mmol, 7.4% yield). ¹H NMR (499 MHz, DMSO-d₆) δppm 2.24 (3H, s), 2.39-2.46 (4H, m), 3.53-3.62 (4H, m), 3.89 (3H, s),6.89 (1H, s), 7.07 (1H, dd, J=5.08, 1.24 Hz), 7.26 (1H, s), 7.60 (1H,dd, J=8.23, 1.65 Hz), 7.81 (1H, d, J=1.65 Hz), 8.03 (1H, s), 8.08 (1H,d, J=8.51 Hz), 8.28-8.33 (2H, m), 10.39 (1H, br s), 11.08 (1H, br s);ESIMS found for C₂₄H₂₆N₅O m/z 444.2 (M+2).

N-(7-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide139

Beige solid (28.0 mg, 0.063 mmol, 63.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, br t, J=4.94 Hz), 2.67 (3H, s),3.57-3.64 (4H, m), 3.94 (3H, s), 7.18 (1H, dd, J=5.08, 1.23 Hz), 7.48(1H, s), 7.58 (1H, d, J=8.51 Hz), 7.79 (1H, d, J=0.82 Hz), 7.95 (1H, d,J=8.78 Hz), 8.10 (1H, s), 8.26 (1H, d, J=5.76 Hz), 8.85 (1H, s), 9.16(1H, s), 11.10 (1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

N-(5-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide140

White solid (20.0 mg, 0.045 mmol, 54.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, br t, J=4.94 Hz), 2.67 (3H, s),3.58-3.63 (4H, m), 3.94 (3H, s), 7.18 (1H, dd, J=5.21, 1.10 Hz), 7.48(1H, s), 7.58 (1H, d, J=8.51 Hz), 7.79 (1H, s), 7.95 (1H, d, J=8.51 Hz),8.10 (1H, s), 8.26 (1H, d, J=5.21 Hz), 8.85 (1H, s), 9.16 (1H, s), 11.10(1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

N-(4-Methyl-6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide141

Off-white solid (16.5 mg, 0.037 mmol, 12.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.40-2.45 (4H, m), 2.51 (3H, br s),3.55-3.63 (4H, m), 3.92 (3H, s), 7.16 (1H, dd, J=5.08, 0.96 Hz), 7.40(1H, s), 7.92 (1H, dd, J=8.51, 1.65 Hz), 8.12 (1H, d, J=8.23 Hz), 8.16(1H, s), 8.23 (1H, s), 8.28 (1H, d, J=4.94 Hz), 8.46 (1H, s), 9.04 (1H,s), 10.73 (1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d₃)piperazin-1-yl)isonicotinamide 142

Beige solid (38.0 mg, 0.088 mmol, 94.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.45 (4H, br s), 3.61 (4H, br s), 3.91 (3H, s), 7.16 (1H,dd, J=5.21, 1.10 Hz), 7.46 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.07(1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d, J=5.21 Hz),8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.04 (1H, s); ESIMS found forC₂₄H₂₂[²H₃]N₇O m/z 431.2 (M+1).

N-(6-(1-(Methyl-d₃)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide143

Beige solid (27.0 mg, 0.063 mmol, 38.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.58-3.63 (4H, m),7.16 (1H, dd, J=5.21, 1.10 Hz), 7.46 (1H, s), 7.81 (1H, dd, J=8.51, 1.65Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d,J=5.21 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.04 (1H, s);ESIMS found for C₂₄H₂₂[²H₃]N₇O m/z 431.2 (M+1).

N-(6-(1-(Methyl-d₃)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d₃)piperazin-1-yl)isonicotinamide 144

Beige solid (30.0 mg, 0.069 mmol, 70.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.42 (4H, br t, J=4.80 Hz), 3.56-3.64 (4H, m), 7.15 (1H,dd, J=5.21, 0.82 Hz), 7.46 (1H, s), 7.81 (1H, dd, J=8.51, 1.37 Hz), 8.07(1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.26 (1H, d, J=5.21 Hz),8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.04 (1H, s); ESIMS found forC₂₄H₁₉[²H₆]N₇O m/z 434.2 (M+1).

N-(6-(1H-Pyrazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d₃)piperazin-1-yl)isonicotinamide 145

White solid (80.0 mg, 0.173 mmol, 37.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.39-2.46 (4H, m), 3.57-3.65 (4H, m), 7.16 (1H, dd,J=5.08, 1.24 Hz), 7.46 (1H, s), 7.88 (1H, dd, J=8.51, 1.65 Hz), 8.07(1H, d, J=8.51 Hz), 8.19 (2H, br s), 8.26 (1H, d, J=4.94 Hz), 8.46 (1H,br s), 8.60 (1H, s), 9.13 (1H, s), 11.04 (1H, s), 13.12 (1H, br s);ESIMS found for C₂₃H₂₀[²H₃]N₇O m/z 417.2 (M+1).

N-(6-(1-(Difluoromethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide146

Beige solid (60.0 mg, 0.130 mmol, 78.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.58-3.64 (4H, m),7.16 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.89 (1H, t, J=59.40 Hz),7.94 (1H, dd, J=8.51, 1.65 Hz), 8.14 (1H, d, J=8.51 Hz), 8.26 (1H, d,J=5.21 Hz), 8.34 (1H, s), 8.52 (1H, s), 8.65 (1H, s), 8.97 (1H, s), 9.18(1H, s), 11.09 (1H, s); ESIMS found for C₂₄H₂₃F₂N₇O m/z 464.2 (M+1).

N-(6-(1-Ethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 147

Off-white solid (25.0 mg, 0.057 mmol, 34.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.44 (3H, t, J=7.27 Hz), 2.23 (3H, s), 2.43 (4H, t,J=5.08 Hz), 3.57-3.64 (4H, m), 4.20 (2H, q, J=7.41 Hz), 7.16 (1H, dd,J=5.21, 1.37 Hz), 7.46 (1H, s), 7.83 (1H, dd, J=8.51, 1.65 Hz), 8.07(1H, d, J=8.78 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.26 (1H, d, J=5.21 Hz),8.45 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 11.04 (1H, s); ESIMS found forC₂₅H₂₇N₇O m/z 442.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide148

Beige solid (53.0 mg, 0.124 mmol, 75.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.58-3.64 (4H, m),3.94 (3H, s), 6.97 (1H, d, J=2.47 Hz), 7.16 (1H, dd, J=4.94, 1.10 Hz),7.47 (1H, s), 7.82 (1H, d, J=2.20 Hz), 8.02-8.08 (1H, m), 8.08-8.13 (1H,m), 8.26 (1H, d, J=4.94 Hz), 8.31 (1H, s), 8.64 (1H, s), 9.17 (1H, s),11.06 (1H, s); ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

N-(6-(5-Amino-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide149

Off-white solid (15.0 mg, 0.034 mmol, 12.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.40-2.46 (4H, m), 3.57-3.62 (4H, m), 3.64(3H, s), 5.72 (2H, s), 7.15 (1H, d, J=4.12 Hz), 7.46 (1H, s), 7.67 (1H,s), 7.72 (1H, dd, J=8.64, 1.51 Hz), 7.93 (1H, s), 7.99 (1H, d, J=8.51Hz), 8.26 (1H, d, J=5.21 Hz), 8.59 (1H, s), 9.06 (1H, s), 10.92 (1H, s);ESIMS found for C₂₄H₂₆N₅O m/z 443.0 (M+1).

4-(Difluoromethoxy)-N-(6-(5-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 151

White solid (11.2 mg, 0.026 mmol, 5.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.94 (3H, s), 4.66 (2H, d, J=5.49 Hz), 5.58 (1H, t, J=5.49 Hz),7.40 (1H, t, J=74.00 Hz), 7.31 (2H, d, J=8.78 Hz), 7.73 (1H, dd, J=8.37,1.51 Hz), 7.84 (1H, s), 8.03 (1H, s), 8.11 (1H, d, J=8.51 Hz), 8.14-8.20(2H, m), 8.63 (1H, s), 9.18 (1H, s), 10.92 (1H, s); ESIMS found forC₂₂H₁₈F₂N₄O₃ m/z 424.9 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide168

White solid (73.0 mg, 0.160 mmol, 45.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.56-3.64 (4H, m),3.94 (3H, s), 4.66 (2H, d, J=5.21 Hz), 5.58 (1H, t, J=5.35 Hz), 7.16(1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.75 (1H, dd, J=8.51, 1.65 Hz),7.84 (1H, s), 8.03 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.26 (1H, d, J=5.21Hz), 8.64 (1H, s), 9.19 (1H, s), 11.08 (1H, s); ESIMS found forC₂₅H₂₇N₇O₂ m/z 458.2 (M+1).

N-(6-(5-(Hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide172

Off-white solid (6.0 mg, 0.012 mmol, 24.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76 (4H, br t, J=5.08 Hz), 2.15 (3H, s), 2.28 (4H, brs), 3.74 (4H, s), 3.94 (3H, s), 4.66 (2H, br d, J=3.84 Hz), 5.54-5.62(1H, m), 7.03 (1H, s), 7.13 (1H, dd, J=5.21, 1.37 Hz), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.84 (1H, s), 8.03 (1H, s), 8.12 (1H, d, J=8.51 Hz),8.20 (1H, d, J=5.21 Hz), 8.62 (1H, s), 9.18 (1H, s), 11.00 (1H, s);ESIMS found for C₂₈H₃₁N₇O₂ m/z 498.3 (M+1).

4-Fluoro-N-(6-(1-methyl-5-(pyrrolidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 182

White solid (15.0 mg, 0.033 mmol, 22.6% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.68 (4H, br t, J=3.02 Hz), 2.43-2.48 (4H, m), 3.85 (2H,s), 3.93 (3H, s), 7.36 (2H, t, J=8.78 Hz), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.05 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.13-8.21 (2H,m), 8.59 (1H, s), 9.16 (1H, s), 10.90 (1H, s); ESIMS found forC₂₅H₂₄FN₅O m/z 430.0 (M+1).

4-Fluoro-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide 183

Beige foam (43.0 mg, 0.092 mmol, 34.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.33-1.42 (2H, m), 1.46-1.55 (4H, m), 2.37 (4H, br s), 3.67 (2H,s), 3.92 (3H, s), 7.35 (2H, t, J=8.92 Hz), 7.74 (1H, dd, J=8.51, 1.37Hz), 7.82 (1H, s), 8.08 (1H, d, J=8.51 Hz), 8.13 (1H, s), 8.14-8.21 (2H,m), 8.60 (1H, s), 9.16 (1H, s), 10.85 (1H, s); ESIMS found forC₂₆H₂₆FN₅O m/z 444.0 (M+1).

4-(Difluoromethoxy)-N-(6-(1-methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)benzamide184

White solid (13.4 mg, 0.026 mmol, 5.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.34-1.43 (2H, m), 1.46-1.55 (4H, m), 2.38 (4H, br s), 3.67 (2H,s), 3.92 (3H, s), 7.40 (2H, t, J=73.70 Hz), 7.31 (2H, d, J=8.51 Hz),7.75 (1H, dd, J=8.51, 1.37 Hz), 7.83 (1H, s), 8.09 (1H, d, J=8.51 Hz),8.14 (1H, s), 8.15-8.20 (2H, m), 8.61 (1H, s), 9.16 (1H, s), 10.90 (1H,s); ESIMS found for C₂₇H₂₇F₂N₅O₂ m/z 491.9 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide185

White solid (35.0 mg, 0.065 mmol, 9.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.34-1.44 (2H, m), 1.47-1.55 (4H, m), 1.71 (4H, dt, J=6.66, 3.12Hz), 2.38 (4H, br s), 2.44-2.49 (4H, m), 3.66 (2H, s), 3.67 (2H, s),3.92 (3H, s), 7.41-7.50 (1H, m), 7.50-7.58 (1H, m), 7.75 (1H, dd,J=8.51, 1.65 Hz), 7.83 (1H, s), 7.95 (1H, d, J=7.68 Hz), 8.00 (1H, s),8.08 (1H, d, J=8.78 Hz), 8.14 (1H, s), 8.60 (1H, s), 9.16 (1H, s), 10.82(1H, s); ESIMS found for C₃₁H₃₆N₆O m/z 509.3 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide186

Off-white solid (8.0 mg, 0.014 mmol, 23.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.39 (2H, br d, J=4.39 Hz), 1.46-1.53 (4H, m), 1.76 (4H,br t, J=5.08 Hz), 2.15 (3H, s), 2.19-2.33 (4H, m), 2.38 (4H, br s), 3.67(2H, s), 3.74 (4H, s), 3.92 (3H, s), 7.03 (1H, s), 7.13 (1H, dd, J=5.21,1.37 Hz), 7.77 (1H, dd, J=8.51, 1.37 Hz), 7.83 (1H, s), 8.09 (1H, d,J=8.51 Hz), 8.15 (1H, s), 8.20 (1H, d, J=5.21 Hz), 8.60 (1H, s), 9.17(1H, s), 10.98 (1H, s); ESIMS found for C₃₃H₄₀N₈O m/z 565.4 (M+1).

N-(6-(1-Methyl-5-(morpholinomethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide204

Off-white solid (10.0 mg, 0.020 mmol, 10.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.42 (4H, br d, J=3.84 Hz), 3.53-3.61 (8H, m), 3.70-3.78(6H, m), 3.94 (3H, s), 7.21 (1H, dd, J=5.21, 1.37 Hz), 7.47 (1H, s),7.76 (1H, dd, J=8.51, 1.65 Hz), 7.83 (1H, s), 8.11 (2H, d, J=11.25 Hz),8.29 (1H, d, J=4.94 Hz), 8.62 (1H, s), 9.18 (1H, s), 11.02 (1H, s);ESIMS found for C₂₈H₃₁N₇O₃ m/z 514.0 (M+1).

4-Fluoro-N-(6-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide219

Off-white solid (20.0 mg, 0.052 mmol, 22.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.18 (2H, br t, J=5.21 Hz), 4.07 (2H, br t, J=5.21 Hz),4.25 (2H, s), 7.33-7.41 (2H, m), 7.68 (1H, dd, J=8.51, 1.37 Hz), 7.86(1H, s), 8.00 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.12-8.21 (2H, m), 8.61(1H, s), 9.13 (1H, s), 10.86 (1H, s); ESIMS found for C₂₂H₁₈FN₅O m/z387.9 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide 220

Yellow solid (2.0 mg, 0.004 mmol, 2.1% yield). ¹H NMR (499 MHz,METHANOL-d₄) δ ppm 2.37 (3H, s), 2.65-2.69 (4H, m), 3.00-3.05 (1H, m),3.14 (4H, dt, J=57.10, 5.50 Hz), 3.33-3.36 (4H, m), 3.70-3.77 (1H, m),4.15 (2H, s), 4.28 (2H, t, J=5.49 Hz), 4.62-4.76 (2H, m), 6.70 (1H, brd, J=6.31 Hz), 7.23 (1H, dd, J=7.96, 2.20 Hz), 7.39-7.46 (1H, m),7.46-7.52 (1H, m), 7.60 (1H, d, J=1.65 Hz), 7.67 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 7.95 (1H, s), 8.59 (1H, s), 9.05 (1H, s); ESIMS foundfor C₂₉H₃₂FN₇O m/z 514.3 (M+1).

N⁵-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-N²-methylpyridine-2,5-dicarboxamide 221

White solid (66.0 mg, 0.139 mmol, 62.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.85 (3H, br d, J=4.39 Hz), 2.94-3.04 (2H, m), 3.08 (2H,br s), 4.10 (2H, s), 4.19 (2H, br s), 4.59-4.75 (2H, m), 7.71 (1H, br d,J=8.51 Hz), 7.87 (1H, s), 8.04 (1H, s), 8.10 (1H, br d, J=8.51 Hz), 8.16(1H, br d, J=7.96 Hz), 8.56 (1H, br d, J=7.68 Hz), 8.66 (1H, s), 8.94(1H, br d, J=4.67 Hz), 9.16 (1H, s), 9.22 (1H, s), 11.31 (1H, s); ESIMSfound for C₂₅H₂₄FN₇O₂ m/z 474.2 (M+1).

N-(6-(5-(2-Fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide 222

Yellow solid (21.0 mg, 0.041 mmol, 11.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.38-2.43 (4H, m), 3.00 (3H, dt, J=28.60,4.70 Hz), 3.09 (2H, br t, J=5.35 Hz), 3.61-3.70 (4H, m), 4.10 (2H, s),4.19 (2H, br t, J=5.35 Hz), 4.67 (2H, dt, J=47.80, 5.00 Hz), 6.90 (1H,d, J=9.06 Hz), 7.66 (1H, dd, J=8.64, 1.51 Hz), 7.81 (1H, s), 8.01 (1H,s), 8.07 (1H, d, J=8.51 Hz), 8.20 (1H, dd, J=9.06, 2.47 Hz), 8.60 (1H,s), 8.85 (1H, d, J=2.47 Hz), 9.12 (1H, s), 10.58 (1H, s); ESIMS foundfor C₂₈H₃₁FN₈O m/z 515.0 (M+1).

2-(Azetidin-3-yloxy)-N-(6-(5-(2-fluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)isoquinolin-3-yl)isonicotinamide223

Beige solid (5.0 mg, 0.010 mmol, 10.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.99 (2H, dt, J=28.60, 5.00 Hz), 3.08 (2H, br t, J=5.35 Hz), 3.71(2H, br d, J=4.67 Hz), 3.96 (2H, br s), 4.10 (2H, s), 4.19 (2H, brt,J=5.35 Hz), 4.67 (2H, dt, J=47.80, 4.70 Hz), 5.41 (1H, quin, J=5.90 Hz),7.43 (1H, s), 7.59 (1H, br d, J=4.67 Hz), 7.71 (1H, dd, J=8.51, 1.65Hz), 7.87 (1H, s), 8.03 (1H, s), 8.10 (1H, d, J=8.51 Hz), 8.31 (1H, d,J=5.21 Hz), 8.63 (1H, s), 9.16 (1H, s), 11.12 (1H, br s); ESIMS foundfor C₂₆H₂₆FN₇O₂ m/z 488.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide230

Off-yellow solid (34.5 mg, 0.074 mmol, 40.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.75 (2H, m), 1.93-2.02 (2H, m), 2.15-2.27 (2H, m),2.20 (3H, s), 2.58-2.67 (2H, m), 4.15 (3H, s), 4.47-4.59 (1H, m), 7.17(1H, ddd, J=8.30, 2.40, 1.10 Hz), 7.42 (1H, t, J=8.10 Hz), 7.59-7.69(2H, m), 8.06 (1H, dd, J=8.51, 1.65 Hz), 8.17 (1H, d, J=8.51 Hz), 8.37(1H, s), 8.65 (1H, s), 8.74 (1H, s), 9.20 (1H, s), 10.83 (1H, s); ESIMSfound for C₂₅H₂₆N₆O₂ m/z 443.0 (M+1).

N²-methyl-N⁵-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)pyridine-2,5-dicarboxamide232

Yellow solid (12.7 mg, 0.033 mmol, 7.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.86 (3H, d, J=4.67 Hz), 4.15 (3H, s), 8.09 (1H, dd,J=8.51, 1.65 Hz), 8.17 (2H, dd, J=12.21, 8.37 Hz), 8.40 (1H, s), 8.57(1H, dd, J=8.10, 2.33 Hz), 8.67 (1H, s), 8.75 (1H, s), 8.89 (1H, q,J=4.48 Hz), 9.22 (2H, s), 11.31 (1H, s); ESIMS found for C₂₀H₁₇N₇O₂ m/z387.9. (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide233

Yellow solid (42.7 mg, 0.100 mmol, 28.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.38-2.43 (4H, m), 3.61-3.68 (4H, m), 4.15(3H, s), 6.89 (1H, d, J=9.06 Hz), 8.04 (1H, dd, J=8.51, 1.65 Hz), 8.14(1H, d, J=8.51 Hz), 8.20 (1H, dd, J=9.06, 2.47 Hz), 8.34 (1H, s), 8.63(1H, s), 8.73 (1H, s), 8.85 (1H, d, J=2.47 Hz), 9.17 (1H, s), 10.64 (1H,s); ESIMS found for C₂₃H₂₄N₅O m/z 429.0 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 236

Beige solid (30.0 mg, 0.070 mmol, 24.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.14 (6H, s), 3.19-3.25 (1H, m), 3.81 (2H, dd, J=8.37,5.35 Hz), 4.07 (2H, t, J=7.68 Hz), 4.15 (3H, s), 7.04 (1H, s), 7.16 (1H,dd, J=5.21, 1.37 Hz), 8.08 (1H, dd, J=8.51, 1.37 Hz), 8.17 (1H, d,J=8.51 Hz), 8.20-8.26 (1H, m), 8.38 (1H, s), 8.64 (1H, s), 8.74 (1H, s),9.20 (1H, s), 10.99 (1H, s); ESIMS found for C₂₃H₂₄N₈O m/z 429.0 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(1-methylpiperidin-4-yl)isonicotinamide238

Off-white solid (36.0 mg, 0.084 mmol, 68.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.77-1.93 (4H, m), 2.00 (2H, td, J=11.53, 2.47 Hz), 2.21(3H, s), 2.73 (1H, tt, J=11.46, 4.05 Hz), 2.90 (2H, br d, J=11.25 Hz),4.15 (3H, s), 7.77 (1H, dd, J=4.94, 1.65 Hz), 7.92 (1H, s), 8.09 (1H,dd, J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.78 Hz), 8.40 (1H, s), 8.67 (1H,s), 8.69 (1H, d, J=5.21 Hz), 8.76 (1H, s), 9.22 (1H, s), 11.23 (1H, s);ESIMS found for C₂₄H₂₅N₇O m/z 428.2 (M+1).

2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 240

White solid (18.0 mg, 0.039 mmol, 28.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.40 (2H, qd, J=11.98, 3.84 Hz), 1.85 (2H, br d, J=11.80Hz), 2.24 (6H, s), 2.37-2.46 (1H, m), 2.81-2.92 (2H, m), 4.15 (3H, s),4.44 (2H, br d, J=13.17 Hz), 7.13 (1H, dd, J=5.08, 0.96 Hz), 7.46 (1H,s), 8.07 (1H, dd, J=8.51, 1.37 Hz), 8.17 (1H, d, J=8.51 Hz), 8.25 (1H,d, J=5.21 Hz), 8.38 (1H, s), 8.65 (1H, s), 8.74 (1H, s), 9.21 (1H, s),11.04 (1H, s); ESIMS found for C₂₅H₂₈N₅O m/z 457.0 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide241

Off-white solid (70.0 mg, 0.169 mmol, 53.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.52-3.63 (4H, m), 3.70-3.78 (4H, m), 4.15 (3H, s), 7.22(1H, dd, J=5.08, 1.23 Hz), 7.47 (1H, s), 8.08 (1H, dd, J=8.51, 1.65 Hz),8.17 (1H, d, J=8.78 Hz), 8.29 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.66(1H, s), 8.74 (1H, s), 9.21 (1H, s), 11.06 (1H, s); ESIMS found forC₂₂H₂₁N₇O₂ m/z 415.9 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide242

White solid (38.0 mg, 0.089 mmol, 37.8% yield). ¹HNMR (499 MHz, DMSO-d₆)δ ppm 2.23 (3H, s), 2.43 (4H, br t, J=4.67 Hz), 3.56-3.66 (4H, m), 4.15(3H, s), 7.17 (1H, d, J=4.94 Hz), 7.47 (1H, s), 8.04-8.10 (1H, m), 8.18(1H, d, J=8.51 Hz), 8.26 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.66 (1H, s),8.75 (1H, s), 9.21 (1H, s), 11.10 (1H, s); ESIMS found for C₂₃H₂₄N₅O m/z429.0 (M+1).

2-(4-Methyl-1,4-diazepan-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 243

Beige solid (47.0 mg, 0.106 mmol, 37.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.93 (2H, dt, J=11.39, 5.83 Hz), 2.27 (3H, s), 2.48 (2H,br s), 2.63 (2H, dd, J=5.63, 4.25 Hz), 3.69 (2H, t, J=6.17 Hz),3.78-3.85 (2H, m), 4.15 (3H, s), 7.06 (1H, dd, J=5.21, 1.10 Hz), 7.21(1H, s), 8.08 (1H, dd, J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.51 Hz), 8.21(1H, d, J=4.94 Hz), 8.38 (1H, s), 8.65 (1H, s), 8.76 (1H, s), 9.21 (1H,s), 11.08 (1H, s); ESIMS found for C₂₄H₂₆N₅O m/z 443.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide 245

Beige solid (198.0 mg, 0.434 mmol, 36.8% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.01 (6H, d, J=6.59 Hz), 2.53-2.59 (4H, m), 2.65-2.75(1H, m), 3.53-3.63 (4H, m), 4.15 (3H, s), 7.16 (1H, dd, J=5.21, 1.37Hz), 7.45 (1H, s), 8.08 (1H, dd, J=8.51, 1.37 Hz), 8.18 (1H, d, J=8.78Hz), 8.26 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.66 (1H, s), 8.76 (1H, s),9.21 (1H, s), 11.11 (1H, s); ESIMS found for C₂₅H₂₈N₅O m/z 457.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperidin-4-ylamino)isonicotinamide249

White solid (7.0 mg, 0.016 mmol, 57.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.33-1.46 (2H, m), 1.93 (2H, br d, J=10.15 Hz), 2.69 (2H, br t,J=10.98 Hz), 3.06 (2H, br d, J=12.62 Hz), 3.81-3.93 (1H, m), 4.15 (3H,s), 6.78 (1H, d, J=7.68 Hz), 7.00 (1H, s), 7.03 (1H, dd, J=5.21, 1.37Hz), 8.07 (1H, dd, J=8.51, 1.37 Hz), 8.10 (1H, d, J=5.49 Hz), 8.17 (1H,d, J=8.51 Hz), 8.39 (1H, s), 8.62 (1H, s), 8.75 (1H, s), 9.20 (1H, s),10.88 (1H, br s); ESIMS found for C₂₃H₂₄N₅O m/z 429.0 (M+1).

2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide250

Brown solid (19.0 mg, 0.042 mmol, 14.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.49-1.64 (2H, m), 1.75-1.87 (2H, m), 2.05 (2H, br t,J=10.84 Hz), 2.20 (3H, s), 2.82-2.90 (2H, m), 2.94 (3H, s), 4.15 (3H,s), 4.45-4.56 (1H, m), 7.08 (1H, dd, J=5.08, 1.23 Hz), 7.19 (1H, s),8.07 (1H, dd, J=8.37, 1.51 Hz), 8.17 (1H, d, J=8.51 Hz), 8.23 (1H, d,J=5.21 Hz), 8.37 (1H, s), 8.65 (1H, s), 8.74 (1H, s), 9.21 (1H, s),11.01 (1H, s); ESIMS found for C₂₅H₂₈N₅O m/z 457.0 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide253

Off-white solid (28.0 mg, 0.061 mmol, 19.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.58-1.72 (2H, m), 1.99-2.07 (2H, m), 2.12 (2H, br t,J=10.29 Hz), 2.17 (3H, s), 2.69 (2H, br d, J=10.70 Hz), 3.84 (1H, br t,J=9.74 Hz), 4.15 (3H, s), 7.64 (1H, dd, J=5.21, 1.65 Hz), 7.82 (1H, s),8.09 (1H, dd, J=8.51, 1.65 Hz), 8.18 (1H, d, J=8.51 Hz), 8.39 (1H, s),8.62 (1H, d, J=5.21 Hz), 8.64 (1H, s), 8.75 (1H, s), 9.21 (1H, s), 11.22(1H, s); ESIMS found for C₂₄H₂₅N₇OS m/z 460.2 (M+1).

2-Methyl-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide256

Off-white solid (39.0 mg, 0.093 mmol, 85.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.37 (3H, s), 2.64 (2H, t, J=5.90 Hz), 2.92 (2H, br t,J=5.76 Hz), 3.56 (2H, s), 4.15 (3H, s), 7.19 (1H, d, J=7.96 Hz), 7.83(1H, dd, J=7.96, 1.92 Hz), 7.88 (1H, s), 8.06 (1H, dd, J=8.51, 1.65 Hz),8.16 (1H, d, J=8.78 Hz), 8.36 (1H, d, J=0.82 Hz), 8.64 (1H, s), 8.74(1H, s), 9.18 (1H, s), 10.69 (1H, s); ESIMS found for C₂₃H₂₂N₆O m/z399.0 (M+1).

N-(7-Fluoro-6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide257

Light brown solid (14.0 mg, 0.031 mmol, 17.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, br t, J=4.94 Hz), 3.57-3.66 (4H,m), 4.17 (3H, s), 7.17 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 8.07(1H, d, J=11.25 Hz), 8.26 (1H, d, J=5.49 Hz), 8.60 (1H, d, J=4.39 Hz),8.67 (1H, d, J=6.86 Hz), 8.71 (1H, s), 9.22 (1H, s), 11.11 (1H, s);ESIMS found for C₂₃H₂₃FN₈O m/z 447.2 (M+1).

N-(6-(1H-1,2,4-Triazol-1-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 258

Beige solid (40.0 mg, 0.097 mmol, 41.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.56-3.66 (4H, m),7.16 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 8.11 (1H, dd, J=8.78, 1.92Hz), 8.26 (1H, d, J=5.21 Hz), 8.32 (1H, d, J=9.06 Hz), 8.35 (1H, s),8.48 (1H, d, J=1.92 Hz), 8.73 (1H, s), 9.29 (1H, s), 9.53 (1H, s), 11.18(1H, s); ESIMS found for C₂₂H₂₂N₅O m/z 415.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-3-(pyrrolidin-1-ylmethyl)benzamide261

White solid (25.0 mg, 0.061 mmol, 27.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.72 (4H, dt, J=6.66, 3.12 Hz), 2.48 (4H, br s), 3.67(2H, s), 3.85 (3H, s), 7.32 (1H, d, J=0.82 Hz), 7.41-7.51 (1H, m), 7.54(1H, br d, J=7.68 Hz), 7.72 (1H, dd, J=8.51, 1.65 Hz), 7.80 (1H, s),7.96 (1H, br d, J=7.96 Hz), 8.01 (1H, s), 8.08 (1H, s), 8.14 (1H, d,J=8.51 Hz), 8.68 (1H, s), 9.21 (1H, s), 10.81 (1H, s); ESIMS found forC₂₅H₂₅N₅O m/z 412.0 (M+1).

2-(Dimethylamino)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 265

White solid (16.0 mg, 0.043 mmol, 14.9% yield). H NMR (499 MHz, DMSO-d₆)δ ppm 3.11 (6H, s), 3.85 (3H, s), 7.09 (1H, dd, J=5.08, 1.23 Hz), 7.25(1H, s), 7.33 (1H, d, J=1.10 Hz), 7.29-7.29 (1H, m), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, d, J=0.82 Hz), 8.15 (1H, d,J=8.51 Hz), 8.23 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.22 (1H, s), 11.07(1H, s); ESIMS found for C₂₁H₂₀N₆O m/z 373.2 (M+1).

2-(3-Aminoazetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide266

Yellow solid (25.3 mg, 0.063 mmol, 51.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.15 (2H, br s), 3.62 (2H, dd, J=8.23, 5.76 Hz),3.79-3.89 (4H, m), 4.19 (2H, t, J=7.68 Hz), 7.02 (1H, s), 7.14 (1H, dd,J=5.21, 1.37 Hz), 7.33 (1H, d, J=1.10 Hz), 7.74 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d, J=8.51 Hz), 8.20 (1H, d,J=5.21 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.04 (1H, br s); ESIMS foundfor C₂₂H₂₁N₇O m/z 400.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)isonicotinamide 268

White solid (69.0 mg, 0.173 mmol, 62.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.94-2.03 (4H, m), 3.47 (4H, br t, J=6.59 Hz), 3.85 (3H,s), 7.06 (1H, dd, J=5.21, 1.37 Hz), 7.08 (1H, s), 7.33 (1H, s), 7.74(1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15 (1H, d,J=8.78 Hz), 8.21 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.22 (1H, s), 11.04(1H, s); ESIMS found for C₂₃H₂₂N₆O m/z 399.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(piperidin-1-yl)isonicotinamide 271

White solid (85.0 mg, 0.206 mmol, 74.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.53-1.62 (4H, m), 1.62-1.69 (2H, m), 3.61-3.66 (4H, m),3.85 (3H, s), 7.09 (1H, dd, J=5.21, 1.37 Hz), 7.33 (1H, s), 7.44 (1H,s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.09 (1H, s), 8.15(1H, d, J=8.51 Hz), 8.23 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.22 (1H, s),11.09 (1H, s); ESIMS found for C₂₄H₂₄N₆O m/z 413.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide273

White solid (70.0 mg, 0.169 mmol, 61.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.54-3.59 (4H, m), 3.71-3.77 (4H, m), 3.85 (3H, s), 7.21(1H, dd, J=5.08, 1.23 Hz), 7.33 (1H, s), 7.48 (1H, s), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.16 (1H, d, J=8.51 Hz),8.29 (1H, d, J=4.94 Hz), 8.70 (1H, s), 9.23 (1H, s), 11.11 (1H, s);ESIMS found for C₂₃H₂₂N₆O₂ m/z 415.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide275

Beige solid (85.0 mg, 0.187 mmol, 64.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.02 (6H, d, J=6.59 Hz), 2.53-2.59 (4H, m), 2.66-2.75(1H, m), 3.52-3.63 (4H, m), 3.85 (3H, s), 7.15 (1H, dd, J=5.08, 1.23Hz), 7.32 (1H, d, J=1.10 Hz), 7.44 (1H, s), 7.73 (1H, dd, J=8.51, 1.65Hz), 7.80 (1H, s), 7.77-7.78 (1H, m), 8.09 (1H, s), 8.15 (1H, d, J=8.51Hz), 8.26 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.22 (1H, s), 11.04 (1H, s);ESIMS found for C₂₆H₂₉N₇O m/z 456.0 (M+1).

2-(4-Cyclopropylpiperazin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 276

White solid (46.0 mg, 0.101 mmol, 73.6% yield). ¹HNMR (500 MHz, DMSO-d₆)δ ppm 0.34-0.41 (2H, m), 0.41-0.49 (2H, m), 1.66 (1H, tt, J=6.62, 3.53Hz), 2.62-2.68 (4H, m), 3.52-3.61 (4H, m), 3.85 (3H, s), 7.15 (1H, dd,J=5.08, 1.23 Hz), 7.33 (1H, d, J=1.10 Hz), 7.47 (1H, s), 7.74 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.15 (1H, d, J=8.78 Hz),8.26 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.23 (1H, s), 11.12 (1H, s);ESIMS found for C₂₆H₂₇N₇O m/z 454.0 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide277

Off-white solid (131.6 mg, 0.290 mmol, 31.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.62-1.71 (4H, m), 2.66 (4H, br s), 3.73 (4H, s), 3.85(3H, s), 7.03 (1H, s), 7.12 (1H, dd, J=5.21, 1.37 Hz), 7.33 (1H, s),7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.15 (1H, d,J=8.51 Hz), 8.20 (1H, d, J=5.21 Hz), 8.68 (1H, s), 9.22 (1H, s), 11.04(1H, br s); ESIMS found for C₂₆H₂₇N₇O m/z 454.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)isonicotinamide278

Off-white solid (39.0 mg, 0.079 mmol, 35.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76 (4H, br t, J=5.08 Hz), 2.14 (3H, s), 2.27 (4H, brs), 3.73 (4H, s), 3.85 (3H, s), 7.03 (1H, s), 7.13 (1H, dd, J=5.08, 1.51Hz), 7.33 (1H, s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10(1H, s), 8.15 (1H, d, J=8.51 Hz), 8.20 (1H, d, J=5.21 Hz), 8.68 (1H, s),9.22 (1H, s), 11.04 (1H, s); ESIMS found for C₂₇H₂₉N₇O m/z 468.2 (M+1).

N-(6-(1-Methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide285

Off-white solid (233.7 mg, 0.633 mmol, 68.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (4H, s), 4.07 (1H, s), 4.27 (3H, s), 7.33 (1H, s),7.44 (1H, d, J=7.96 Hz), 7.72 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s),7.97 (1H, dd, J=7.82, 1.24 Hz), 8.01 (1H, s), 8.09 (1H, s), 8.14 (1H, d,J=8.51 Hz), 8.69 (1H, s), 9.21 (1H, s), 10.84 (1H, s); ESIMS found forC₂₂H₁₉N₅O m/z 370.2 (M+1).

2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide286

Off-white solid (39.0 mg, 0.097 mmol, 17.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.51 (3H, br s), 3.85 (3H, s), 3.87 (4H, s), 7.33 (1H,s), 7.37 (1H, d, J=7.96 Hz), 7.72 (1H, dd, J=8.64, 1.51 Hz), 7.81 (1H,s), 7.89-7.98 (2H, m), 8.09 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.68 (1H,s), 9.20 (1H, s), 10.80 (1H, s); ESIMS found for C₂₃H₂₁N₅O m/z 384.2(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide289

Beige solid (37.0 mg, 0.085 mmol, 35.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.54-3.61 (4H, m), 3.68 (3H, s), 3.70-3.77(4H, m), 7.14 (1H, s), 7.21 (1H, dd, J=5.08, 1.23 Hz), 7.47 (1H, s),7.67 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.78 Hz),8.29 (1H, d, J=4.94 Hz), 8.67 (1H, s), 9.21 (1H, s), 11.05 (1H, s);ESIMS found for C₂₄H₂₄N₆O₂ m/z 429.0 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)-7-fluoroisoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide290

Off-white solid (54.0 mg, 0.118 mmol, 42.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.41 (3H, s), 2.41-2.45 (4H, m), 3.54 (3H,d, J=0.82 Hz), 3.58-3.63 (4H, m), 7.07 (1H, d, J=0.82 Hz), 7.15 (1H, dd,J=5.21, 1.10 Hz), 7.47 (1H, s), 8.05 (1H, d, J=10.43 Hz), 8.08 (1H, d,J=7.14 Hz), 8.26 (1H, d, J=5.21 Hz), 8.71 (1H, s), 9.23 (1H, s), 11.14(1H, s); ESIMS found for C₂₅H₂₆FN₇O m/z 460.2 (M+1).

4-Fluoro-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide291

Beige solid (55.0 mg, 0.142 mmol, 83.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.79 (1H, br s), 3.09 (2H, t, J=5.21 Hz), 3.96 (2H, s),4.14 (2H, t, J=5.21 Hz), 7.31 (1H, s), 7.36 (2H, t, J=8.78 Hz), 7.71(1H, dd, J=8.64, 1.51 Hz), 8.03 (1H, s), 8.11 (1H, d, J=8.51 Hz),8.14-8.21 (2H, m), 8.67 (1H, s), 9.18 (1H, s), 10.92 (1H, s); ESIMSfound for C₂₂H₁₈FN₅O m/z 387.9 (M+1).

4-(Difluoromethoxy)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)benzamide 292

Yellow solid (12.7 mg, 0.029 mmol, 12.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.78 (1H, br s), 3.09 (2H, br t, J=5.21 Hz), 3.96 (2H,s), 4.14 (2H, t, J=5.35 Hz), 7.40 (1H, t, J=73.70 Hz), 7.31 (3H, t,J=4.25 Hz), 7.71 (1H, dd, J=8.51, 1.65 Hz), 8.03 (1H, s), 8.12 (1H, d,J=8.51 Hz), 8.14-8.20 (2H, m), 8.68 (1H, s), 9.19 (1H, s), 10.93 (1H,s); ESIMS found for C₂₃H₁₉F₂N₅O₂ m/z 435.9 (M+1).

2-((2-(Dimethylamino)ethyl)amino)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)isonicotinamide293

Beige solid (8.0 mg, 0.018 mmol, 11.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.20 (6H, s), 2.44 (2H, brt, J=6.59 Hz), 3.09 (2H, brt, J=5.35Hz), 3.39 (2H, q, J=6.31 Hz), 3.96 (2H, s), 4.13 (2H, br t, J=5.35 Hz),6.57 (1H, br t, J=5.63 Hz), 7.03 (1H, dd, J=5.21, 1.37 Hz), 7.05 (1H,s), 7.31 (1H, s), 7.72 (1H, dd, J=8.64, 1.51 Hz), 8.03 (1H, s), 8.11(2H, d, J=6.04 Hz), 8.64 (1H, s), 9.17 (1H, s), 10.79 (1H, br s); ESIMSfound for C₂₅H₂₈N₅O m/z 457.0 (M+1).

2-((1-Isopropylpiperidin-4-yl)oxy)-N-(6-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-3-yl)isoquinolin-3-yl)isonicotinamide294

Beige solid (22.0 mg, 0.043 mmol, 21.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 0.99 (6H, d, J=6.59 Hz), 1.60-1.72 (2H, m), 1.95-2.04(2H, m), 2.30-2.39 (2H, m), 2.68-2.84 (4H, m), 3.08 (2H, br t, J=5.21Hz), 3.96 (2H, s), 4.14 (2H, t, J=5.35 Hz), 5.02 (1H, tt, J=8.54, 4.08Hz), 7.32 (1H, s), 7.35 (1H, s), 7.50 (1H, dd, J=5.49, 1.37 Hz), 7.73(1H, dd, J=8.64, 1.51 Hz), 8.05 (1H, s), 8.12 (1H, d, J=8.51 Hz), 8.31(1H, d, J=5.21 Hz), 8.66 (1H, s), 9.19 (1H, s), 11.10 (1H, s); ESIMSfound for C₂₉H₃₃N₇O₂ m/z 512.3 (M+1).

4-(Difluoromethoxy)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)benzamide 296

Brown solid (16.1 mg, 0.042 mmol, 7.4% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 7.41 (1H, t, J=73.60 Hz), 7.29-7.34 (2H, m), 7.92 (1H, dd, J=8.51,1.65 Hz), 7.98 (1H, s), 8.14-8.22 (3H, m), 8.29 (1H, s), 8.59 (1H, s),8.69 (1H, s), 9.22 (1H, s), 10.99 (1H, s); ESIMS found for C₂₀H₁₃F₂N₃O₃m/z 381.9 (M+1).

3-((1-Methylpiperidin-4-yl)oxy)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)benzamide 301

Yellow solid (35.1 mg, 0.078 mmol, 58.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.61-1.75 (2H, m), 1.92-2.02 (2H, m), 2.14-2.25 (2H, m),2.19 (3H, s), 2.58-2.67 (2H, m), 4.48-4.59 (1H, m), 7.14-7.21 (1H, m),7.42 (1H, t, J=8.10 Hz), 7.61-7.68 (2H, m), 7.92 (1H, dd, J=8.51, 1.65Hz), 7.98 (1H, s), 8.19 (1H, d, J=8.51 Hz), 8.29 (1H, s), 8.24-8.25 (1H,m), 8.60 (1H, s), 8.69 (1H, s), 9.22 (1H, s), 10.93 (1H, s); ESIMS foundfor C₂₅H₂₄N₄O₃ m/z 429.1 (M+1).

2-(3-Aminoazetidin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 306

Yellow solid (5.1 mg, 0.013 mmol, 3.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.62 (2H, dd, J=8.23, 5.76 Hz), 3.85 (1H, quin, J=6.38 Hz), 4.19(2H, t, J=7.68 Hz), 7.01 (1H, s), 7.14 (1H, dd, J=5.21, 1.37 Hz), 7.94(1H, dd, J=8.51, 1.65 Hz), 7.98 (1H, s), 8.19 (1H, d, J=2.47 Hz), 8.21(1H, s), 8.29 (1H, s), 8.59 (1H, s), 8.68 (1H, s), 9.23 (1H, s), 11.07(1H, br s); ESIMS found for C₂₁H₁₈N₆O₂ m/z 387.2 (M+1).

2-(1-Methylpiperidin-4-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 309

Off-white solid (15.0 mg, 0.036 mmol, 51.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.78-1.92 (4H, m), 2.00 (2H, td, J=11.53, 2.47 Hz), 2.21(3H, s), 2.73 (1H, tt, J=11.49, 4.15 Hz), 2.90 (2H, br d, J=11.25 Hz),7.77 (1H, dd, J=5.21, 1.65 Hz), 7.92 (1H, s), 7.94 (1H, dd, J=8.51, 1.65Hz), 7.98 (1H, s), 8.20 (1H, d, J=8.51 Hz), 8.31 (1H, s), 8.60 (1H, s),8.69 (1H, d, J=4.94 Hz), 8.70 (1H, s), 9.24 (1H, s), 11.26 (1H, s);ESIMS found for C₂₄H₂₃N₅O₂ m/z 414.2 (M+1).

1′-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide310

Tan solid (51.0 mg, 0.124 mmol, 54.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.31 (3H, s), 2.56-2.63 (2H, m), 2.65 (2H, br d, J=2.74 Hz), 3.11(2H, br d, J=3.02 Hz), 6.89 (1H, br s), 7.78 (1H, dd, J=4.94, 1.37 Hz),7.94 (1H, dd, J=8.51, 1.65 Hz), 7.98 (1H, s), 8.17 (1H, s), 8.21 (1H, d,J=8.51 Hz), 8.31 (1H, s), 8.59 (1H, s), 8.65-8.75 (2H, m), 9.24 (1H, s),11.33 (1H, s); ESIMS found for C₂₄H₂₁N₅O₂ m/z 412.2 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide 313

Brown solid (13.0 mg, 0.031 mmol, 19.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.55-3.64 (4H, m),7.16 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.93 (1H, dd, J=8.51, 1.65Hz), 7.98 (1H, s), 8.20 (1H, d, J=8.51 Hz), 8.26 (1H, d, J=4.94 Hz),8.30 (1H, s), 8.59 (1H, s), 8.69 (1H, s), 9.23 (1H, s), 11.13 (1H, s);ESIMS found for C₂₃H₂₂N₆O₂ m/z 415.2 (M+1).

2-(7-Methyl-2,7-diazaspiro[3.5]nonan-2-yl)-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isonicotinamide317

Off-white solid (24.0 mg, 0.050 mmol, 57.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.76 (4H, br t, J=5.08 Hz), 2.15 (3H, s), 2.27 (4H, brs), 3.74 (4H, s), 7.03 (1H, s), 7.13 (1H, dd, J=5.35, 1.51 Hz), 7.94(1H, dd, J=8.51, 1.65 Hz), 7.98 (1H, s), 8.19 (1H, d, J=2.74 Hz), 8.21(1H, s), 8.30 (1H, s), 8.59 (1H, s), 8.68 (1H, s), 9.23 (1H, s), 11.06(1H, s); ESIMS found for C₂₆H₂₆N₆O₂ m/z 455.2 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(2,7-diazaspiro [3.5]nonan-7-yl)isonicotinamide 318

Beige solid (9.0 mg, 0.020 mmol, 50.2% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.74 (4H, br s), 3.27 (4H, br s), 3.58 (4H, br d, J=4.67 Hz), 7.11(1H, br d, J=4.67 Hz), 7.46 (1H, s), 7.94 (1H, dd, J=8.51, 1.37 Hz),7.98 (1H, s), 8.20 (1H, d, J=8.51 Hz), 8.24 (1H, d, J=4.94 Hz), 8.30(1H, s), 8.60 (1H, s), 8.69 (1H, s), 9.24 (1H, s), 11.13 (1H, br s);ESIMS found for C₂₅H₂₄N₆O₂ m/z 441.2 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-2-(piperidin-4-ylamino)isonicotinamide319

White solid (18.0 mg, 0.043 mmol, 8.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 1.65-1.76 (2H, m), 2.04-2.13 (2H, m), 2.97-3.07 (2H, m), 3.25-3.30(2H, m), 4.05 (1H, br s), 7.09 (1H, br d, J=4.12 Hz), 7.93 (1H, dd,J=8.51, 1.65 Hz), 7.98 (1H, s), 8.12 (1H, d, J=5.49 Hz), 8.19 (1H, d,J=8.78 Hz), 8.31 (1H, s), 8.59 (1H, s), 8.65 (1H, s), 8.99 (2H, br s),9.22 (1H, s), 10.94 (1H, br s); ESIMS found for C₂₃H₂₂N₆O₂ m/z 415.2(M+1).

2-Methyl-N-(6-(oxazol-5-yl)isoquinolin-3-yl)isoindoline-5-carboxamide325

Off-white solid (39.0 mg, 0.100 mmol, 57.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.51 (3H, br s), 3.88 (4H, s), 7.37 (1H, d, J=7.96 Hz),7.88-7.96 (3H, m), 7.98 (1H, s), 8.18 (1H, d, J=8.78 Hz), 8.29 (1H, s),8.59 (1H, s), 8.68 (1H, s), 9.21 (1H, s), 10.83 (1H, s); ESIMS found forC₂₂H₂₈N₄O₂ m/z 371.1 (M+1).

N-(6-(Oxazol-5-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide326

Off-white solid (17.0 mg, 0.046 mmol, 26.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.74-2.81 (2H, m), 2.99 (2H, br t, J=5.76 Hz), 3.90-3.96(2H, m), 7.22 (1H, d, J=7.96 Hz), 7.80 (1H, s), 7.81-7.85 (1H, m), 7.91(1H, dd, J=8.51, 1.65 Hz), 7.98 (1H, s), 8.18 (1H, d, J=8.78 Hz), 8.28(1H, s), 8.59 (1H, s), 8.68 (1H, s), 9.21 (1H, s), 10.76 (1H, s); ESIMSfound for C₂₂H₁₈N₄O₂ m/z 371.2 (M+1).

N-(6-(2-Methyloxazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 328

Beige solid (149.0 mg, 0.348 mmol, 74.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.43 (4H, t, J=4.94 Hz), 2.55 (3H, s),3.56-3.66 (4H, m), 7.16 (1H, dd, J=5.21, 1.10 Hz), 7.46 (1H, s), 7.82(1H, s), 7.88 (1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.78 Hz), 8.20(1H, s), 8.26 (1H, d, J=5.21 Hz), 8.66 (1H, s), 9.20 (1H, s), 11.11 (1H,s); ESIMS found for C₂₄H₂₄N₆O₂ m/z 429.2 (M+1).

N-(6-(5-Methyl-1,3,4-oxadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide329

Beige solid (20.0 mg, 0.047 mmol, 19.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.43 (4H, br t, J=4.80 Hz), 2.65 (3H, s),3.56-3.67 (4H, m), 7.17 (1H, dd, J=5.08, 1.23 Hz), 7.47 (1H, s), 8.11(1H, dd, J=8.51, 1.65 Hz), 8.27 (1H, d, J=4.94 Hz), 8.30 (1H, d, J=8.51Hz), 8.58 (1H, s), 8.78 (1H, s), 9.34 (1H, s), 11.20 (1H, s); ESIMSfound for C₂₃H₂₃N₇O₂ m/z 430.0 (M+1).

N-(6-(5-Chlorothiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 330

Yellow solid (1.3 mg, 0.003 mmol, 1.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (3H, s), 2.40-2.46 (4H, m), 3.58-3.64 (4H, m), 7.10-7.20 (1H,m), 7.46 (1H, s), 7.89 (1H, dd, J=8.64, 1.78 Hz), 8.18 (1H, d, J=8.23Hz), 8.26 (1H, d, J=5.21 Hz), 8.28 (1H, s), 8.38 (1H, s), 8.69 (1H, s),9.24 (1H, s), 11.09 (1H, s); ESIMS found for C₂₃H₂₁ClN₆OS m/z 464.9(M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(5-methylthiazol-2-yl)isoquinolin-3-yl)isonicotinamide 331

Off-yellow solid (11.5 mg, 0.026 mmol, 9.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.38-2.47 (4H, m), 2.56 (3H, d, J=1.10 Hz),3.56-3.66 (4H, m), 7.17 (1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.73(1H, d, J=1.37 Hz), 8.09 (1H, dd, J=8.51, 1.65 Hz), 8.19 (1H, d, J=8.51Hz), 8.26 (1H, d, J=5.21 Hz), 8.43 (1H, s), 8.71 (1H, s), 9.25 (1H, s),11.09 (1H, s); ESIMS found for C₂₄H₂₄N₆OS m/z 444.9 (M+1).

2-(4-Methylpiperazil-1-yl)-N-(6-(4-methylthiazol-2-yl)isoquinolin-3-yl)isonicotinamide 332

Black solid (23.6 mg, 0.053 mmol, 18.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.40-2.46 (4H, m), 2.49 (3H, br s),3.55-3.65 (4H, m), 7.17 (1H, dd, J=5.08, 1.24 Hz), 7.46 (1H, br s), 7.47(1H, d, J=0.82 Hz), 8.11 (1H, dd, J=8.51, 1.65 Hz), 8.20 (1H, d, J=8.51Hz), 8.26 (1H, d, J=4.94 Hz), 8.49 (1H, s), 8.72 (1H, s), 9.26 (1H, s),11.09 (1H, s); ESIMS found for C₂₄H₂₄N₆OS m/z 444.9 (M+1).

2-(3-(2-(4-Methylpiperazin-1-yl)isonicotinamido)isoquinolin-6-yl)thiazole-5-carboxamide333

Yellow solid (7.6 mg, 0.016 mmol, 5.8% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (3H, s), 2.41-2.45 (4H, m), 3.58-3.64 (4H, m), 7.17 (1H, dd,J=5.08, 1.23 Hz), 7.47 (1H, s), 7.69 (1H, br s), 8.15 (1H, dd, J=8.64,1.78 Hz), 8.24 (2H, br d, J=8.78 Hz), 8.27 (1H, d, J=4.94 Hz), 8.54 (1H,s), 8.60 (1H, s), 8.75 (1H, s), 9.29 (1H, s), 11.13 (1H, s); ESIMS foundfor C₂₄H₂₃N₇O₂S m/z 473.9 (M+1).

6-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)nicotinamide334

White solid (64.1 mg, 0.149 mmol, 42.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.37-2.45 (4H, m), 3.60-3.68 (4H, m), 6.90(1H, d, J=9.06 Hz), 7.89 (1H, dd, J=8.51, 1.92 Hz), 8.14 (1H, d, J=8.51Hz), 8.20 (1H, dd, J=9.06, 2.47 Hz), 8.25 (1H, d, J=0.82 Hz), 8.57 (1H,s), 8.66 (1H, s), 8.85 (1H, d, J=2.47 Hz), 9.19 (2H, d, J=2.47 Hz),10.66 (1H, s); ESIMS found for C₂₃H₂₂N₆OS m/z 430.9 (M+1).

1′-Methyl-N-(6-(thiazol-5-yl)isoquinolin-3-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide335

Off-white solid (7.6 mg, 0.018 mmol, 33.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.31 (3H, s), 2.56-2.63 (2H, m), 2.63-2.69 (2H, m), 3.11(2H, br d, J=3.02 Hz), 6.85-6.93 (1H, m), 7.78 (1H, dd, J=4.94, 1.37Hz), 7.94 (1H, dd, J=8.51, 1.65 Hz), 8.13-8.22 (2H, m), 8.32 (1H, d,J=0.82 Hz), 8.60 (1H, s), 8.71 (2H, dd, J=3.43, 1.51 Hz), 9.21 (1H, s),9.24 (1H, s), 11.33 (1H, s); ESIMS found for C₂₄H₂₁N₅OS m/z 428.2 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 336

Beige solid (15.0 mg, 0.035 mmol, 12.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.14 (6H, s), 3.19-3.25 (1H, m), 3.81 (2H, dd, J=8.23,5.21 Hz), 4.07 (2H, t, J=7.68 Hz), 7.04 (1H, s), 7.15 (1H, dd, J=5.21,1.37 Hz), 7.93 (1H, dd, J=8.51, 1.65 Hz), 8.17 (1H, d, J=8.78 Hz), 8.21(1H, d, J=5.21 Hz), 8.30 (1H, s), 8.58 (1H, s), 8.67 (1H, s), 9.20 (1H,s), 9.22 (1H, s), 11.01 (1H, s); ESIMS found for C₂₃H₂₂N₆OS m/z 430.9(M+1).

2-(4-(Dimethylamino)piperidin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 337

Off-white solid (390.0 mg, 0.851 mmol, 80.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.31-1.46 (2H, m), 1.84 (2H, br d, J=10.70 Hz), 2.19 (6H,s), 2.34 (1H, ddd, J=10.98, 7.41, 3.29 Hz), 2.88 (2H, br t, J=11.80 Hz),4.44 (2H, br d, J=12.62 Hz), 7.05-7.15 (1H, m), 7.46 (1H, s), 7.93 (1H,dd, J=8.51, 1.65 Hz), 8.17 (1H, d, J=8.51 Hz), 8.24 (1H, d, J=5.21 Hz),8.31 (1H, s), 8.59 (1H, s), 8.69 (1H, s), 9.21 (1H, s), 9.23 (1H, s),11.12 (1H, s); ESIMS found for C₂₅H₂₆N₆OS m/z 459.2 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 338

Off-yellow solid (42.9 mg, 0.100 mmol, 42.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.37-2.46 (4H, m), 3.55-3.66 (4H, m), 7.16(1H, d, J=4.12 Hz), 7.46 (1H, s), 7.92 (1H, dd, J=8.51, 1.65 Hz), 8.17(1H, d, J=8.51 Hz), 8.26 (1H, d, J=5.21 Hz), 8.30 (1H, s), 8.58 (1H, s),8.68 (1H, s), 9.20 (1H, s), 9.22 (1H, s), 11.07 (1H, s); ESIMS found forC₂₃H₂₂N₆OS m/z 430.9 (M+1).

2-((1-Methylpiperidin-4-yl)thio)-N-(6-(thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 339

Off-white solid (54.7 mg, 0.119 mmol, 41.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.58-1.74 (2H, m), 1.98-2.07 (2H, m), 2.12 (2H, br t,J=10.15 Hz), 2.17 (3H, s), 2.65-2.75 (2H, m), 3.79-3.90 (1H, m), 7.64(1H, dd, J=5.08, 1.51 Hz), 7.82 (1H, s), 7.94 (1H, dd, J=8.51, 1.65 Hz),8.17 (1H, d, J=8.51 Hz), 8.32 (1H, s), 8.59 (1H, s), 8.62 (1H, d, J=5.21Hz), 8.68 (1H, s), 9.21 (1H, s), 9.23 (1H, s), 11.24 (1H, s); ESIMSfound for C₂₄H₂₃N₅OS₂ m/z 462.1 (M+1).

N-(6-(Thiazol-5-yl)isoquinolin-3-yl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide340

Off-white solid (57.3 mg, 0.148 mmol, 39.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.73-2.80 (2H, m), 2.98 (2H, br t, J=5.76 Hz), 3.93 (2H,s), 7.22 (1H, d, J=8.23 Hz), 7.71 (1H, br d, J=5.76 Hz), 7.79 (1H, s),7.89-7.96 (1H, m), 8.16 (1H, d, J=8.78 Hz), 8.29 (1H, s), 8.59 (1H, s),8.67 (1H, s), 9.20 (2H, s), 10.75 (1H, s); ESIMS found for C₂₂H₁₈N₄OSm/z 387.1 (M+1).

N-(6-(2-Aminothiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 359

Off-yellow solid (3.8 mg, 0.009 mmol, 3.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.40-2.44 (4H, m), 3.57-3.64 (4H, m), 7.15(1H, dd, J=5.08, 1.24 Hz), 7.33-7.38 (2H, m), 7.45 (1H, s), 7.71 (1H,s), 7.73-7.80 (2H, m), 8.01 (1H, d, J=8.23 Hz), 8.26 (1H, d, J=4.94 Hz),8.55 (1H, s), 9.09 (1H, s), 10.98 (1H, s); ESIMS found for C₂₃H₂₃N₇OSm/z 445.9 (M+1).

2-(3-Aminoazetidin-1-yl)-N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide373

Yellow solid (21.5 mg, 0.048 mmol, 39.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.13 (6H, s), 3.63 (2H, dd, J=8.23, 5.76 Hz), 3.85 (1H,quin, J=6.45 Hz), 4.19 (2H, t, J=7.82 Hz), 7.00 (1H, s), 7.13 (1H, dd,J=5.21, 1.37 Hz), 7.80 (1H, dd, J=8.64, 1.78 Hz), 7.85 (1H, s), 7.91(1H, s), 8.03 (1H, d, J=8.51 Hz), 8.19 (1H, d, J=5.21 Hz), 8.54 (1H, s),9.10 (1H, s), 10.97 (1H, s); ESIMS found for C₂₃H₂₃N₇OS m/z 446.1 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 374

Yellow solid (10.3 mg, 0.022 mmol, 5.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.13 (6H, s), 2.90 (3H, d, J=4.67 Hz), 3.19-3.26 (1H, m),3.80 (2H, dd, J=8.37, 5.35 Hz), 4.06 (2H, t, J=7.68 Hz), 7.03 (1H, s),7.14 (1H, dd, J=5.21, 1.37 Hz), 7.77-7.80 (2H, m), 7.81 (1H, s), 7.95(1H, q, J=4.67 Hz), 8.02 (1H, d, J=8.23 Hz), 8.21 (1H, d, J=5.21 Hz),8.54 (1H, s), 9.09 (1H, s), 10.97 (1H, s); ESIMS found for C₂₄H₂₅N₇OSm/z 460.2 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(2-(dimethylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 375

Yellow solid (34.6 mg, 0.073 mmol, 27.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.13 (6H, s), 3.13 (6H, s), 3.18-3.26 (1H, m), 3.80 (2H,dd, J=8.51, 5.21 Hz), 4.06 (2H, t, J=7.68 Hz), 7.03 (1H, s), 7.15 (1H,dd, J=5.21, 1.37 Hz), 7.79 (1H, dd, J=8.51, 1.65 Hz), 7.84 (1H, s), 7.90(1H, s), 8.02 (1H, d, J=8.51 Hz), 8.20 (1H, d, J=5.49 Hz), 8.54 (1H, s),9.09 (1H, s), 10.98 (1H, br s); ESIMS found for C₂₅H₂₇N₇OS m/z 474.2(M+1).

N-(6-(2-(Methylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide376

Yellow solid (59.0 mg, 0.128 mmol, 29.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.42 (4H, br t, J=4.94 Hz), 2.90 (3H, d,J=4.67 Hz), 3.56-3.63 (4H, m), 7.15 (1H, dd, J=5.08, 1.23 Hz), 7.46 (1H,s), 7.76-7.80 (2H, m), 7.81 (1H, s), 7.95 (1H, q, J=4.57 Hz), 8.02 (1H,d, J=8.51 Hz), 8.25 (1H, d, J=5.21 Hz), 8.55 (1H, s), 9.10 (1H, s),11.03 (1H, s); ESIMS found for C₂₄H₂₅N₇OS m/z 460.2 (M+1).

N-(6-(2-(Dimethylamino)thiazol-5-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide377

Yellow solid (25.6 mg, 0.054 mmol, 11.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.20-2.27 (3H, m), 2.39-2.47 (4H, m), 3.09-3.20 (6H, m),3.55-3.66 (4H, m), 7.15 (1H, dd, J=4.94, 1.10 Hz), 7.46 (1H, s), 7.80(1H, dd, J=8.64, 1.78 Hz), 7.85 (1H, s), 7.91 (1H, s), 8.03 (1H, d,J=8.51 Hz), 8.25 (1H, d, J=5.21 Hz), 8.56 (1H, s), 9.10 (1H, s), 11.03(1H, s); ESIMS found for C₂₅H₂₇N₇OS m/z 474.2 (M+1).

2-(4-Isopropylpiperazin-1-yl)-N-(6-(2-(methylamino)thiazol-5-yl)isoquinolin-3-yl)isonicotinamide 378

Yellow solid (53.8 mg, 0.110 mmol, 35.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.02 (6H, br d, J=6.04 Hz), 2.56 (4H, br s), 2.70 (1H, brs), 2.90 (3H, d, J=4.67 Hz), 3.58 (4H, br s), 7.14 (1H, d, J=4.67 Hz),7.44 (1H, s), 7.75-7.81 (2H, m), 7.81 (1H, s), 7.95 (1H, q, J=4.85 Hz),8.02 (1H, d, J=8.51 Hz), 8.25 (1H, d, J=4.94 Hz), 8.55 (1H, s), 9.10(1H, s), 11.03 (1H, s); ESIMS found for C₂₆H₂₉N₇OS m/z 488.2 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(2-methylthiazol-5-yl)isoquinolin-3-yl)isonicotinamide 379

Off-yellow solid (44.4 mg, 0.100 mmol, 42.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.38-2.46 (4H, m), 2.73 (3H, s), 3.55-3.66(4H, m), 7.16 (1H, dd, J=5.08, 0.96 Hz), 7.46 (1H, s), 7.85 (1H, dd,J=8.51, 1.65 Hz), 8.13 (1H, d, J=8.51 Hz), 8.17 (1H, s), 8.26 (1H, d,J=5.21 Hz), 8.29 (1H, s), 8.65 (1H, s), 9.19 (1H, s), 11.05 (1H, s);ESIMS found for C₂₄H₂₄N₆OS m/z 444.9 (M+1).

6-(4-Methylpiperazin-1-yl)-N-(6-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)nicotinamide 380

White solid (5.2 mg, 0.010 mmol, 6.9% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.23 (3H, s), 2.40 (4H, br t, J=4.80 Hz), 3.60-3.71 (4H, m), 6.91(1H, d, J=9.06 Hz), 8.21 (2H, dd, J=8.64, 1.78 Hz), 8.30 (1H, d, J=8.51Hz), 8.76 (1H, s), 8.80 (1H, s), 8.86 (1H, d, J=2.20 Hz), 9.34 (1H, s),10.84 (1H, s); ESIMS found for C₂₃H₂₀F₃N₇OS m/z 500.1 (M+1).

2-(4-Methylpiperazin-1-yl)-N-(6-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 381

White solid (4.0 mg, 0.008 mmol, 3.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (3H, s), 2.43 (4H, br t, J=4.80 Hz), 3.55-3.65 (4H, m), 7.17(1H, dd, J=5.21, 1.10 Hz), 7.48 (1H, s), 8.21-8.26 (1H, m), 8.27 (1H, d,J=5.21 Hz), 8.30-8.37 (1H, m), 8.82 (2H, d, J=8.51 Hz), 9.37 (1H, s),11.25 (1H, s); ESIMS found for C₂₃H₂₀F₃N₇OS m/z 500.1 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-(difluoromethoxy)benzamide 382

White solid (5.0 mg, 0.013 mmol, 6.2% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 7.41 (2H, t, J=73.70 Hz), 7.32 (2H, d, J=8.78 Hz), 8.16-8.19 (2H,m), 8.20-8.23 (1H, m), 8.26-8.32 (1H, m), 8.66 (1H, s), 8.79 (1H, s),9.32 (1H, s), 9.75 (1H, s), 11.07 (1H, s); ESIMS found for C₁₉H₁₂F₂N₄O₂Sm/z 398.8 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-3-(4-methylpiperazin-1-yl)benzamide 383

Yellow solid (9.4 mg, 0.022 mmol, 4.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (2H, s), 2.46-2.49 (4H, m), 3.23-3.29 (4H, m), 7.10-7.21 (1H,m), 7.36 (1H, t, J=7.96 Hz), 7.46-7.53 (1H, m), 7.62-7.70 (1H, m),8.16-8.24 (1H, m), 8.24-8.32 (1H, m), 8.64 (1H, d, J=0.82 Hz), 8.79 (1H,s), 9.31 (1H, s), 9.74 (1H, s), 10.96 (1H, s); ESIMS found forC₂₃H₂₂N₆OS m/z 431.9 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-(piperidin-4-yloxy)benzamide 384

White solid (15.7 mg, 0.036 mmol, 69.1% yield). ¹HNMR (499 MHz, DMSO-d₆)δ ppm 1.41-1.54 (2H, m), 1.95 (2H, br dd, J=8.64, 3.16 Hz), 2.56-2.66(2H, m), 2.96 (2H, dt, J=12.49, 3.91 Hz), 4.49-4.60 (1H, m), 7.01-7.10(2H, m), 8.01-8.14 (2H, m), 8.14-8.23 (1H, m), 8.23-8.32 (1H, m), 8.63(1H, s), 8.78 (1H, s), 9.30 (1H, s), 9.74 (1H, s), 10.80 (1H, s); ESIMSfound for C₂₃H₂₁N₅O₅₂S m/z 432.1 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-4-((1-methylpiperidin-4-yl)oxy)benzamide 385

Off-yellow solid (17.7 mg, 0.038 mmol, 40.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.73 (2H, m), 1.97 (2H, br dd, J=9.47, 3.98 Hz),2.16-2.24 (2H, m), 2.18 (3H, s), 2.57-2.69 (2H, m), 4.52 (1H, tt,J=8.13, 3.95 Hz), 7.07 (2H, d, J=9.06 Hz), 8.03-8.14 (2H, m), 8.14-8.23(1H, m), 8.23-8.30 (1H, m), 8.64 (1H, s), 8.78 (1H, s), 9.30 (1H, s),9.74 (1H, s), 10.82 (1H, s); ESIMS found for C₂₄H₂₃N₅O₅₂S m/z 445.9(M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide 386

Yellow solid (162.0 mg, 0.345 mmol, 24.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.76 (2H, m), 1.93-2.03 (2H, m), 2.18-2.25 (2H, m),2.19 (3H, s), 2.57-2.68 (2H, m), 4.53 (1H, tt, J=7.99, 3.95 Hz), 7.18(1H, ddd, J=8.23, 2.47, 1.10 Hz), 7.43 (1H, t, J=8.10 Hz), 7.62-7.70(2H, m), 8.16-8.24 (1H, m), 8.24-8.32 (1H, m), 8.65 (1H, d, J=0.82 Hz),8.79 (1H, s), 9.32 (1H, s), 9.75 (1H, s), 10.99 (1H, s); ESIMS found forC₂₄H₂₃N₅O₅₂S m/z 446.2 (M+1).

N⁵-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-N²-methylpyridine-2,5-dicarboxamide387

White solid (5.2 mg, 0.013 mmol, 6.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.86 (3H, d, J=4.94 Hz), 8.16 (1H, d, J=7.96 Hz), 8.20-8.27 (1H,m), 8.27-8.32 (1H, m), 8.57 (1H, dd, J=8.23, 2.20 Hz), 8.69 (1H, s),8.82 (1H, s), 8.95 (1H, q, J=4.57 Hz), 9.23 (1H, d, J=1.37 Hz), 9.34(1H, s), 9.75 (1H, s), 11.47 (1H, s); ESIMS found for C₁₉H₁₄N₆O₂S m/z391.1 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-6-(4-methylpiperazin-1-yl)nicotinamide 388

Brown solid (14.1 mg, 0.033 mmol, 10.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.22 (3H, s), 2.40 (4H, t, J=5.08 Hz), 3.60-3.71 (4H, m),6.91 (1H, d, J=9.06 Hz), 8.14-8.23 (2H, m), 8.23-8.30 (1H, m), 8.62 (1H,s), 8.76 (1H, s), 8.86 (1H, d, J=2.47 Hz), 9.30 (1H, s), 9.74 (1H, s),10.80 (1H, s); ESIMS found for C₂₂H₂₁N₇OS m/z 431.9 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-1′-methyl-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide389

White solid (2.5 mg, 0.006 mmol, 5.7% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.31 (3H, s), 2.58-2.63 (2H, m), 2.64-2.69 (2H, m), 3.08-3.15 (2H,m), 6.90 (1H, t, J=3.43 Hz), 7.79 (1H, dd, J=4.94, 1.37 Hz), 8.18 (1H,s), 8.21-8.26 (1H, m), 8.26-8.35 (1H, m), 8.64-8.74 (2H, m), 8.82 (1H,s), 9.35 (1H, s), 9.75 (1H, s), 11.41 (1H, br s); ESIMS found forC₂₃H₂₀N₆OS m/z 429.1 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(3-(dimethylamino)azetidin-1-yl)isonicotinamide390

White solid (15.0 mg, 0.035 mmol, 10.1% yield). ¹HNMR (499 MHz, DMSO-d₆)δ ppm 2.14 (6H, s), 3.17-3.26 (1H, m), 3.81 (2H, dd, J=8.37, 5.35 Hz),4.07 (2H, t, J=7.55 Hz), 7.05 (1H, s), 7.16 (1H, dd, J=5.21, 1.10 Hz),8.18-8.25 (2H, m), 8.25-8.33 (1H, m), 8.66 (1H, s), 8.78 (1H, s), 9.33(1H, s), 9.75 (1H, s), 11.15 (1H, s); ESIMS found for C₂₂H₂₁N₇OS m/z432.1 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide 391

White solid (15.2 mg, 0.035 mmol, 9.6% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.24 (3H, s), 2.44 (4H, br d, J=4.12 Hz), 3.61 (4H, br s), 7.17(1H, br d, J=4.94 Hz), 7.47 (1H, s), 8.18-8.25 (1H, m), 8.25-8.33 (2H,m), 8.65 (1H, s), 8.78 (1H, s), 9.32 (1H, s), 9.69-9.78 (1H, m), 11.15(1H, br s); ESIMS found for C₂₂H₂₁N₇OS m/z 431.9 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-isopropylpiperazin-1-yl)isonicotinamide 392

Yellow solid (10.1 mg, 0.022 mmol, 16.1% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.02 (6H, d, J=6.59 Hz), 2.52-2.60 (4H, m), 2.66-2.76(1H, m), 3.53-3.64 (4H, m), 7.16 (1H, dd, J=5.21, 1.37 Hz), 7.46 (1H,s), 8.18-8.25 (1H, m), 8.26 (1H, d, J=5.21 Hz), 8.27-8.32 (1H, m), 8.67(1H, d, J=0.82 Hz), 8.80 (1H, s), 9.33 (1H, s), 9.75 (1H, s), 11.20 (1H,s); ESIMS found for C₂₄H₂₅N₇OS m/z 460.2 (M+1).

N-(6-(1,3,4-Thiadiazol-2-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide393

Beige solid (10.0 mg, 0.024 mmol, 8.0% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.54-3.60 (4H, m), 3.69-3.76 (4H, m), 7.22 (1H, dd, J=5.21, 1.10Hz), 7.48 (1H, s), 8.18-8.25 (1H, m), 8.25-8.33 (2H, m), 8.67 (1H, s),8.80 (1H, s), 9.33 (1H, s), 9.75 (1H, s), 11.21 (1H, s); ESIMS found forC₂₁H₁₈N₆O₂S m/z 419.1 (M+1).

2-(3-(Dimethylamino)azetidin-1-yl)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 406

Beige solid (20.0 mg, 0.045 mmol, 25.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.13 (6H, s), 2.84 (3H, s), 3.17-3.26 (1H, m), 3.81 (2H,dd, J=8.51, 5.49 Hz), 4.07 (2H, t, J=7.55 Hz), 7.05 (1H, s), 7.16 (1H,dd, J=5.21, 1.37 Hz), 8.16 (1H, dd, J=8.51, 1.65 Hz), 8.22 (1H, d,J=4.94 Hz), 8.26 (1H, d, J=8.78 Hz), 8.55 (1H, s), 8.76 (1H, s), 9.31(1H, s), 11.14 (1H, s); ESIMS found for C₂₃H₂₃N₇OS m/z 446.2 (M+1).

1′-Methyl-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-1′,2′,3′,6′-tetrahydro-[2,4′-bipyridine]-4-carboxamide409

Off-white solid (2.6 g, 5.87 mmol, 56.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.31 (3H, s), 2.56-2.63 (2H, m), 2.63-2.69 (2H, m), 2.84(3H, s), 3.08-3.16 (2H, m), 6.89 (1H, dt, J=3.29, 1.92 Hz), 7.79 (1H,dd, J=4.94, 1.65 Hz), 8.12-8.22 (2H, m), 8.26 (1H, d, J=8.78 Hz), 8.57(1H, d, J=0.82 Hz), 8.72 (1H, d, J=4.94 Hz), 8.80 (1H, s), 9.33 (1H, s),11.39 (1H, s); ESIMS found for C₂₄H₂₂N₆OS m/z 443.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide412

Beige solid (35.0 mg, 0.079 mmol, 38.3% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.41-2.46 (4H, m), 2.84 (3H, s), 3.55-3.66(4H, m), 7.16 (1H, dd, J=5.21, 1.10 Hz), 7.48 (1H, s), 8.16 (1H, dd,J=8.51, 1.65 Hz), 8.20-8.30 (2H, m), 8.55 (1H, s), 8.78 (1H, s), 9.31(1H, s), 11.20 (1H, s); ESIMS found for C₂₃H₂₃N₇OS m/z 446.2 (M+1).

2-(Methyl(1-methylpiperidin-4-yl)amino)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide419

Beige solid (35.0 mg, 0.074 mmol, 36.0% yield). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.49-1.61 (2H, m), 1.80 (2H, qd, J=12.12, 3.70 Hz),1.98-2.08 (2H, m), 2.19 (3H, s), 2.86 (2H, br d, J=11.53 Hz), 2.93 (3H,s), 4.50 (1H, ddt, J=11.66, 7.89, 3.95, 3.95 Hz), 7.08 (1H, dd, J=5.21,1.37 Hz), 7.19 (1H, s), 8.16 (1H, dd, J=8.51, 1.65 Hz), 8.23 (1H, d,J=5.21 Hz), 8.25 (1H, d, J=8.78 Hz), 8.55 (1H, s), 8.77 (1H, s), 9.31(1H, s), 11.16 (1H, s); ESIMS found for C₂₅H₂₇N₇OS m/z 474.2 (M+1).

2-(Azetidin-3-yloxy)-N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)isonicotinamide 420

Beige solid (4.0 mg, 0.010 mmol, 10.1% yield). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 2.84 (3H, s), 3.50-3.59 (2H, m), 3.72-3.81 (2H, m), 5.35-5.45 (1H,m), 7.41 (1H, s), 7.55 (1H, dd, J=5.49, 1.37 Hz), 8.17 (1H, dd, J=8.51,1.65 Hz), 8.26 (1H, d, J=8.51 Hz), 8.31 (1H, d, J=5.49 Hz), 8.57 (1H,s), 8.77 (1H, s), 9.32 (1H, s), 11.26 (1H, br s); ESIMS found forC₂₁H₁₈N₆O₂S m/z 419.1 (M+1).

N-(6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-3-((1-methylpiperidin-4-yl)oxy)benzamide422

Yellow solid (22.8 mg, 0.047 mmol, 10.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.63-1.74 (2H, m), 1.93-2.00 (2H, m), 2.16-2.24 (2H, m),2.19 (3H, s), 2.56-2.69 (2H, m), 2.84 (3H, s), 4.53 (1H, tt, J=8.03,3.91 Hz), 7.18 (1H, ddd, J=8.16, 2.40, 0.96 Hz), 7.43 (1H, t, J=8.10Hz), 7.59-7.69 (2H, m), 8.15 (1H, dd, J=8.51, 1.65 Hz), 8.25 (1H, d,J=8.78 Hz), 8.54 (1H, d, J=0.82 Hz), 8.77 (1H, s), 9.30 (1H, s), 10.98(1H, s); ESIMS found for C₂₅H₂₅N₅O₂S m/z 460.2 (M+1).

N-(6-(5-Methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-((1-methylpiperidin-4-yl)thio)isonicotinamide423

Light yellow solid (44.0 mg, 0.092 mmol, 33.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.60-1.72 (2H, m), 1.98-2.07 (2H, m), 2.12 (2H, brt,J=10.43 Hz), 2.17 (3H, s), 2.69 (2H, br d, J=10.98 Hz), 2.84 (3H, s),3.84 (1H, brt, J=10.15 Hz), 7.64 (1H, dd, J=5.21, 1.37 Hz), 7.82 (1H,s), 8.17 (1H, dd, J=8.51, 1.65 Hz), 8.26 (1H, d, J=8.51 Hz), 8.56 (1H,s), 8.62 (1H, d, J=5.21 Hz), 8.76 (1H, s), 9.31 (1H, s), 11.30 (1H, s);ESIMS found for C₂₄H₂₄N₆OS₂ m/z 477.1 (M+1).

N-(7-Fluoro-6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide427

Off-white solid (15.0 mg, 0.032 mmol, 17.9% yield). ¹¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.39-2.45 (4H, m), 2.86 (3H, s), 3.58-3.64(4H, m), 7.16 (1H, dd, J=5.21, 1.37 Hz), 7.47 (1H, s), 8.20 (1H, d,J=11.25 Hz), 8.26 (1H, d, J=4.94 Hz), 8.23-8.24 (1H, m), 8.79 (1H, s),8.84 (1H, d, J=7.14 Hz), 9.30 (1H, s), 11.20 (1H, s); ESIMS found forC₂₃H₂₂FN₇OS m/z 464.2 (M+1).

N-(6-(5-(Dimethylamino)-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide428

Yellow solid (14.6 mg, 0.031 mmol, 26.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.32 (3H, br s), 2.52-2.67 (4H, m), 3.19 (6H, s), 3.64(4H, br s), 7.14-7.21 (1H, m), 7.48 (1H, s), 8.07 (1H, dd, J=8.51, 1.65Hz), 8.17 (1H, s), 8.24-8.29 (2H, m), 8.70 (1H, s), 9.24 (1H, s), 11.14(1H, s); ESIMS found for C₂₄H₂₆N₈OS m/z 475.2 (M+1).

N-(6-(1-Methyl-5-(piperidin-1-ylmethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-morpholinoisonicotinamide429

White solid (23.0 mg, 0.045 mmol, 25.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.32-1.44 (2H, m), 1.45-1.55 (4H, m), 2.38 (4H, br s),3.53-3.62 (4H, m), 3.67 (2H, s), 3.71-3.77 (4H, m), 3.92 (3H, s), 7.21(1H, dd, J=5.21, 1.10 Hz), 7.47 (1H, s), 7.76 (1H, dd, J=8.51, 1.65 Hz),7.82 (1H, s), 8.09 (1H, d, J=8.51 Hz), 8.14 (1H, s), 8.29 (1H, d, J=5.21Hz), 8.61 (1H, s), 9.17 (1H, s), 11.01 (1H, s); ESIMS found forC₂₉H₃₃N₇O₂ m/z 512.0 (M+1).

N-(6-(5-Amino-1,3,4-thiadiazol-2-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide430

Yellow solid (3.7 mg, 0.008 mmol, 5.4% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.27 (3H, br s), 3.62 (4H, br s), 7.12-7.20 (1H, m), 7.48 (1H, s),7.60 (2H, s), 8.07 (1H, dd, J=8.51, 1.65 Hz), 8.16 (1H, d, J=8.78 Hz),8.25 (1H, s), 8.27 (1H, d, J=4.94 Hz), 8.71 (1H, s), 9.24 (1H, s), 11.13(1H, s); ESIMS found for C₂₂H₂₂N₅OS m/z 447.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(piperazin-1-yl)isonicotinamide 431

Beige solid (76.0 mg, 0.183 mmol, 42.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.77-2.85 (4H, m), 3.50-3.58 (4H, m), 4.15 (3H, s), 7.14(1H, dd, J=5.21, 1.10 Hz), 7.43 (1H, s), 8.08 (1H, dd, J=8.51, 1.37 Hz),8.18 (1H, d, J=8.51 Hz), 8.25 (1H, d, J=5.21 Hz), 8.38 (1H, s), 8.66(1H, s), 8.76 (1H, s), 9.21 (1H, s), 11.09 (1H, s); ESIMS found forC₂₂H₂₂N₈O m/z 415.2 (M+1).

2-(Azetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 432

Off-white solid (73.7 mg, 0.192 mmol, 66.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.31-2.41 (2H, m), 3.85 (3H, s), 4.03 (4H, t, J=7.41 Hz),7.01 (1H, d, J=0.82 Hz), 7.15 (1H, dd, J=5.21, 1.65 Hz), 7.33 (1H, d,J=1.10 Hz), 7.74 (1H, dd, J=8.37, 1.78 Hz), 7.81 (1H, s), 8.09 (1H, s),8.15 (1H, d, J=8.51 Hz), 8.21 (1H, d, J=5.21 Hz), 8.68 (1H, s), 9.22(1H, s), 11.04 (1H, s); ESIMS found for C₂₂H₂₀N₆O m/z 385.2 (M+1).

2-Methoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 433

Off-white solid (28.0 mg, 0.078 mmol, 34.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.85 (3H, s), 3.93 (3H, s), 7.33 (1H, s), 7.42 (1H, d,J=1.37 Hz), 7.55 (1H, dd, J=5.21, 1.37 Hz), 7.75 (1H, dd, J=8.51, 1.65Hz), 7.81 (1H, s), 8.11 (1H, d, J=0.82 Hz), 8.16 (1H, d, J=8.51 Hz),8.35 (1H, d, J=5.21 Hz), 8.69 (1H, s), 9.23 (1H, s), 11.16 (1H, s);ESIMS found for C₂₀H₁₇N₅O₂ m/z 360.1 (M+1).

2-Methyl-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide434

Off-white solid (32.1 mg, 0.094 mmol, 41.9% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.58 (3H, s), 3.85 (3H, s), 7.33 (1H, d, J=0.82 Hz),7.71-7.78 (2H, m), 7.81 (1H, s), 7.86 (1H, s), 8.12 (1H, s), 8.16 (1H,d, J=8.51 Hz), 8.64 (1H, d, J=4.94 Hz), 8.69 (1H, s), 9.23 (1H, s),11.14 (1H, s); ESIMS found for C₂₀H₁₇N₅O m/z 344.1 (M+1).

2-Cyano-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide435

Off-white solid (36.0 mg, 0.102 mmol, 45.6% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.86 (3H, s), 7.34 (1H, d, J=0.82 Hz), 7.77 (1H, dd,J=8.51, 1.65 Hz), 7.81 (1H, s), 8.14 (1H, s), 8.17 (1H, d, J=8.51 Hz),8.26 (1H, dd, J=4.94, 1.65 Hz), 8.60 (1H, d, J=0.82 Hz), 8.70 (1H, s),8.93-8.99 (1H, m), 9.24 (1H, s), 11.44 (1H, s); ESIMS found forC₂₀H₁₄N₆O m/z 355.1 (M+1).

5-Chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide436

Off-white solid (18.7 mg, 0.041 mmol, 67.2% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.21 (3H, s), 2.39 (4H, br t, J=4.94 Hz), 3.49-3.58 (4H,m), 3.91 (3H, s), 7.08 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.05(1H, d, J=8.78 Hz), 8.11 (1H, s), 8.16 (1H, s), 8.19 (1H, s), 8.38 (1H,s), 8.55 (1H, s), 9.08 (1H, s), 11.15 (1H, s); ESIMS found forC₂₄H₂₄ClN₇O m/z 462.2 (M+1).

2-(3,3-Difluoroazetidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide437

White solid (11.5 mg, 0.027 mmol, 9.5% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 3.85 (3H, s), 4.49 (4H, t, J=12.49 Hz), 7.24 (1H, s), 7.31 (1H,dd, J=5.21, 1.37 Hz), 7.33 (1H, s), 7.75 (1H, dd, J=8.64, 1.51 Hz), 7.81(1H, s), 8.10 (1H, s), 8.16 (1H, d, J=8.51 Hz), 8.31 (1H, d, J=5.21 Hz),8.69 (1H, s), 9.23 (1H, s), 11.11 (1H, s); ESIMS found for C₂₂H₁₈F₂N₆Om/z 421.1 (M+1).

2-(4,4-Bis(methyl-d₃)-4λ4-piperazin-1-yl)-N-(6-(1-methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)isonicotinamide438

Beige solid (62.0 mg, 0.108 mmol, 74.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.53 (4H, t, J=5.21 Hz), 3.94-4.04 (4H, m), 4.15 (3H, s),7.32 (1H, dd, J=5.21, 1.10 Hz), 7.61 (1H, s), 8.08 (1H, dd, J=8.64, 1.51Hz), 8.19 (1H, d, J=8.78 Hz), 8.35 (1H, d, J=5.21 Hz), 8.40 (1H, s),8.68 (1H, s), 8.76 (1H, s), 9.23 (1H, s), 11.13 (1H, s); ESIMS found forC₂₄H₂₁[²H₆]N₅O m/z 449.3 (M+).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(4-(methyl-d₃)piperazin-1-yl)isonicotinamide 439

Beige solid (44.0 mg, 0.102 mmol, 35.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.43 (4H, t, J=4.94 Hz), 3.56-3.63 (4H, m), 4.15 (3H, s),7.17 (1H, dd, J=5.08, 0.96 Hz), 7.47 (1H, s), 8.08 (1H, dd, J=8.37, 1.51Hz), 8.18 (1H, d, J=8.51 Hz), 8.26 (1H, d, J=5.21 Hz), 8.38 (1H, s),8.66 (1H, s), 8.76 (1H, s), 9.21 (1H, s), 11.11 (1H, s); ESIMS found forC₂₃H₂₁[²H₃]N₈O m/z 432. (M+1).

3-Chloro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide440

Off-white solid (90.7 mg, 0.196 mmol, 29.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.24 (3H, s), 2.49 (4H, br s), 3.26-3.31 (4H, m), 3.91(3H, s), 7.17 (1H, d, J=4.67 Hz), 7.81 (1H, dd, J=8.51, 1.65 Hz), 8.05(1H, d, J=8.51 Hz), 8.11 (1H, s), 8.17 (1H, s), 8.29 (1H, d, J=4.67 Hz),8.38 (1H, s), 8.55 (1H, s), 9.07 (1H, s), 11.21 (1H, s); ESIMS found forC₂₄H₂₄ClN₇O m/z 462.2 (M+1).

2-(4,4-Difluoropiperidin-1-yl)-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide441

White solid (18.9 mg, 0.042 mmol, 24.4% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.99-2.09 (4H, m), 3.81 (4H, br d, J=5.76 Hz), 3.85 (3H,s), 7.19 (1H, dd, J=5.21, 1.10 Hz), 7.33 (1H, d, J=0.82 Hz), 7.58 (1H,s), 7.74 (1H, dd, J=8.51, 1.65 Hz), 7.81 (1H, s), 8.10 (1H, s), 8.16(1H, d, J=8.51 Hz), 8.29 (1H, d, J=5.21 Hz), 8.70 (1H, s), 9.23 (1H, s),11.14 (1H, s); ESIMS found for C₂₄H₂₂F₂N₆O m/z 449.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)isonicotinamide442

Off-white solid (74.4 mg, 0.161 mmol, 59.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.77 (1H, br d, J=9.06 Hz), 1.90 (1H, br d, J=8.78 Hz),2.30 (3H, s), 2.48 (1H, br s), 2.86 (1H, dd, J=9.47, 1.78 Hz), 3.34 (1H,dd, J=9.88, 2.20 Hz), 3.49 (1H, br s), 3.57 (1H, br d, J=9.88 Hz), 3.91(3H, s), 4.70 (1H, br s), 7.05 (1H, dd, J=5.21, 1.37 Hz), 7.11 (1H, s),7.81 (1H, dd, J=8.64, 1.51 Hz), 8.07 (1H, d, J=8.51 Hz), 8.09-8.16 (2H,m), 8.19 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s),10.98 (1H, s); ESIMS found for C₂₅H₂₅N₇O m/z 440.2 (M+1).

2-Isopropoxy-N-(6-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)isonicotinamide 443

Off-white solid (94.6 mg, 0.244 mmol, 54.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.33 (6H, d, J=6.31 Hz), 3.85 (3H, s), 5.30 (1H, spt,J=6.17 Hz), 7.30 (1H, s), 7.33 (1H, d, J=0.82 Hz), 7.50 (1H, dd, J=5.21,1.37 Hz), 7.75 (1H, dd, J=8.37, 1.78 Hz), 7.81 (1H, s), 8.11 (1H, s),8.15 (1H, d, J=8.51 Hz), 8.32 (1H, d, J=5.21 Hz), 8.68 (1H, s), 9.22(1H, s), 11.11 (1H, s); ESIMS found for C₂₂H₂₁N₅O₂ m/z 388.2 (M+1).

2-(2,5-Diazabicyclo[2.2.1]heptan-2-yl)-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)isonicotinamide 444

Off-white solid (145.0 mg, 0.324 mmol, 88.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.71 (1H, br d, J=9.06 Hz), 1.82 (1H, br d, J=9.33 Hz),2.86 (1H, br d, J=9.61 Hz), 2.96 (1H, br d, J=8.78 Hz), 3.29 (1H, br s),3.52 (1H, dd, J=9.33, 1.37 Hz), 3.75 (1H, br s), 3.91 (3H, s), 4.76 (1H,br s), 7.07 (1H, d, J=4.94 Hz), 7.12 (1H, br s), 7.81 (1H, dd, J=8.51,1.65 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.13 (1H, s), 8.19 (1H,d, J=4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 9.12 (1H, s), 10.97 (1H, s);ESIMS found for C₂₄H₂₃N₇O m/z 426.2 (M+1).

N-(6-(1-Methyl-1H-1,2,3-triazol-4-yl)isoquinolin-3-yl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetamide445

Beige solid (2.0 mg, 0.005 mmol, 3.1% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.22 (3H, s), 2.40 (4H, br t, J=4.94 Hz), 3.45-3.51 (4H, m), 3.71(2H, s), 4.13 (3H, s), 6.66 (1H, d, J=4.67 Hz), 6.83 (1H, s), 8.01-8.06(2H, m), 8.12 (1H, d, J=8.78 Hz), 8.28 (1H, s), 8.46 (1H, s), 8.72 (1H,s), 9.13 (1H, s), 10.85 (1H, s); ESIMS found for C₂₄H₂₆N₅O m/z 443.2(M+1).

3-Fluoro-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(4-methylpiperazin-1-yl)isonicotinamide454

Off-white solid (85.9 mg, 0.193 mmol, 24.0% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.42-2.47 (4H, m), 3.41-3.49 (4H, m), 3.91(3H, s), 7.05 (1H, t, J=4.39 Hz), 7.82 (1H, dd, J=8.51, 1.65 Hz), 8.06(1H, d, J=8.51 Hz), 8.08 (1H, d, J=4.94 Hz), 8.11 (1H, s), 8.16 (1H, s),8.38 (1H, s), 8.55 (1H, s), 9.09 (1H, s), 11.17 (1H, s); ESIMS found forC₂₄H₂₄FN₇O m/z 446.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-((4-methylpiperazin-1-yl)methyl)isonicotinamide455

Off-white solid (12.5 mg, 0.028 mmol, 15.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.17 (3H, s), 2.36 (4H, dt, J=3.77, 2.09 Hz), 2.42-2.49(4H, m), 3.68 (2H, s), 3.91 (3H, s), 7.83 (1H, dd, J=13.45, 1.65 Hz),7.83 (1H, d, J=1.65 Hz), 7.95 (1H, s), 8.07 (1H, d, J=8.51 Hz), 8.12(1H, s), 8.15 (1H, s), 8.39 (1H, s), 8.59 (1H, s), 8.68 (1H, d, J=4.94Hz), 9.13 (1H, s), 11.18 (1H, s); ESIMS found for C₂₅H₂₇N₇O m/z 442.2(M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(morpholinomethyl)isonicotinamide 456

Off-white solid (13.6 mg, 0.032 mmol, 80.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.47 (4H, br s), 3.59-3.65 (4H, m), 3.69 (2H, s), 3.91(3H, s), 7.83 (1H, br dd, J=16.47, 1.65 Hz), 7.83-7.84 (1H, m), 7.98(1H, s), 8.08 (1H, d, J=8.51 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.39 (1H,s), 8.59 (1H, s), 8.69 (1H, d, J=4.94 Hz), 9.13 (1H, s), 11.19 (1H, s);ESIMS found for C₂₄H₂₄N₆O₂ m/z 429.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-ylmethyl)isonicotinamide 457

Off-white solid (12.0 mg, 0.029 mmol, 80.7% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.74 (4H, dt, J=6.52, 3.19 Hz), 2.56 (4H, br s), 3.82(2H, s), 3.91 (3H, s), 7.81-7.84 (2H, m), 7.96 (1H, s), 8.07 (1H, d,J=8.51 Hz), 8.12 (1H, s), 8.15 (1H, s), 8.39 (1H, s), 8.59 (1H, s), 8.67(1H, d, J=4.94 Hz), 9.13 (1H, s), 11.19 (1H, s); ESIMS found forC₂₄H₂₄N₆O m/z 413.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-2-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)acetamide458

Beige solid (10.0 mg, 0.023 mmol, 5.3% yield). ¹H NMR (499 MHz, DMSO-d₆)δ ppm 2.21 (3H, s), 2.37-2.42 (4H, m), 3.43-3.49 (4H, m), 3.70 (2H, s),3.89 (3H, s), 6.66 (1H, d, J=4.94 Hz), 6.83 (1H, s), 7.76 (1H, dd,J=8.51, 1.65 Hz), 8.01 (1H, d, J=8.51 Hz), 8.03-8.05 (2H, m), 8.08 (1H,s), 8.35 (1H, s), 8.39 (1H, s), 9.04 (1H, s), 10.77 (1H, s); ESIMS foundfor C₂₅H₂₇N₇O m/z 442.2 (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(4-methylpiperazin-1-yl)isonicotinamide459

Off-white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.23 (3H, s), 2.43 (4H, t, J=4.94 Hz), 3.56-3.64 (4H, m),3.91 (3H, s), 7.16 (1H, dd, J=5.08, 1.24 Hz), 7.46 (1H, s), 7.81 (1H,dd, J=8.64, 1.51 Hz), 8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H,s), 8.26 (1H, d, J=4.94 Hz), 8.38 (1H, s), 8.59 (1H, s), 11.04 (1H, s);ESIMS found for C₂₄H₂₄[²H]N₇O m/z 429. (M+1).

N-(6-(1-Methyl-1H-pyrazol-4-yl)isoquinolin-3-yl-1-d)-2-(piperazin-1-yl)isonicotinamide 461

Off-white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.77-2.84 (4H, m), 3.48-3.57 (4H, m), 3.91 (3H, s), 7.13(1H, dd, J=5.08, 1.24 Hz), 7.42 (1H, s), 7.81 (1H, dd, J=8.51, 1.65 Hz),8.07 (1H, d, J=8.51 Hz), 8.11 (1H, s), 8.14 (1H, s), 8.25 (1H, d, J=5.21Hz), 8.38 (1H, s), 8.59 (1H, s), 11.03 (1H, s); ESIMS found forC₂₃H₂₂[²H]N₇O m/z 415. (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-indazole-5-carboxamide462

Light yellow solid (32.0 mg, 0.084 mmol, 18.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.92 (3H, s), 4.11 (3H, s), 7.75 (1H, d, J=9.06 Hz), 7.80(1H, dd, J=8.51, 1.65 Hz), 8.06 (1H, d, J=8.51 Hz), 8.12 (1H, dd,J=8.92, 1.51 Hz), 8.12 (1H, s), 8.14 (1H, s), 8.24 (1H, s), 8.38 (1H,s), 8.62 (2H, s), 9.12 (1H, s), 10.82 (1H, s); ESIMS found for C₂₂H₁₈N₆Om/z 383.15 (M+1).

1-Methyl-N-(6-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)-1H-benzo[d]imidazole-5-carboxamide463

Light yellow solid (35.6 mg, 0.093 mmol, 20.8% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 3.90 (3H, s), 3.92 (3H, s), 7.70 (1H, d, J=8.51 Hz), 7.79(1H, dd, J=8.51, 1.65 Hz), 8.06 (2H, d, J=8.51 Hz), 8.11 (1H, s), 8.13(1H, s), 8.33 (1H, s), 8.38 (1H, s), 8.47 (1H, d, J=1.65 Hz), 8.62 (1H,s), 9.12 (1H, s), 10.78 (1H, s); ESIMS found for C₂₂H₁₈N₆O m/z 383.2(M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(pyrrolidin-1-yl)isonicotinamide 464

Off-white solid (51.7 mg, 0.125 mmol, 45.3% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 1.95-2.01 (4H, m), 2.40 (3H, s), 3.45-3.51 (4H, m), 3.68(3H, s), 7.06 (1H, dd, J=5.21, 1.37 Hz), 7.08 (1H, s), 7.14 (1H, s),7.67 (1H, dd, J=8.51, 1.65 Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.78 Hz),8.17-8.23 (1H, m), 8.67 (1H, s), 9.22 (1H, s), 11.03 (1H, s); ESIMSfound for C₂₄H₂₄N₆O m/z 413.2 (M+1).

N-(6-(1,2-Dimethyl-1H-imidazol-5-yl)isoquinolin-3-yl)-2-(dimethylamino)isonicotinamide 465

Off-white solid (69.0 mg, 0.179 mmol, 64.5% yield). ¹H NMR (499 MHz,DMSO-d₆) δ ppm 2.40 (3H, s), 3.11 (6H, s), 3.68 (3H, s), 7.09 (1H, dd,J=5.21, 1.10 Hz), 7.14 (1H, s), 7.25 (1H, s), 7.67 (1H, dd, J=8.51, 1.65Hz), 8.00 (1H, s), 8.14 (1H, d, J=8.51 Hz), 8.23 (1H, d, J=4.94 Hz),8.68 (1H, s), 9.22 (1H, s), 11.07 (1H, s); ESIMS found for C₂₂H₂₂N₆₀Om/z 387.2 (M+1).

Example 4

The screening assay for Wnt activity is described as follows. Reportercell lines can be generated by stably transducing cancer cell lines(e.g., colon cancer) or primary cells (e.g., IEC-6 intestinal cells)with a lentiviral construct that includes a Wnt-responsive promoterdriving expression of the firefly luciferase gene.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 10-point dose-response curves starting from 10 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%. ForSp5-Luc reporter gene assays, the cells were plated at 4,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for 36 to 48 hours at 37°C. and 5% CO₂. Following incubation, 15 μl of BriteLite Plusluminescence reagent (Perkin Elmer) was added to each well of the384-well assay plates. The plates were placed on an orbital shaker for 2min and then luminescence was quantified using the Envision (PerkinElmer) plate reader. Readings were normalized to DMSO only treatedcells, and normalized activities were utilized for EC₅₀ calculationsusing the dose-response log (inhibitor) vs. response-variable slope(four parameters) nonlinear regression feature available in GraphPadPrism 5.0 (or Dotmatics). For EC₅₀ of >10 μM, the percent inhibition at10 M is provided.

Table 2 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 2 Compound EC₅₀ (μM) 1 0.067 2 0.091 3 0.116 4 0.370 5 0.089 60.070 7 0.113 8 0.170 9 0.039 10 0.046 11 0.116 12 0.487 13 0.171 140.153 15 >10 (8.0%) 16 0.062 17 0.058 18 0.200 19 0.066 20 0.705 210.745 22 2.109 23 0.425 24 >10 (0%) 25 >10 (48.8%) 26 3.785 27 4.362 280.472 29 0.307 37 0.033 40 0.684 45 0.449 47 3.357 49 0.098 52 1.003 530.039 54 0.035 55 0.032 56 0.031 57 0.109 59 0.062 60 0.680 61 0.182 620.127 63 0.108 64 0.298 65 0.422 66 0.047 67 0.057 71 0.044 72 0.062 740.052 76 0.295 78 0.776 80 0.597 84 0.021 85 0.034 86 0.162 87 3.639 880.131 89 3.376 90 0.132 91 0.107 92 0.103 93 0.036 94 0.110 95 >10(3.5%) 97 0.041 99 0.041 100 8.409 101 1.041 102 0.979 103 2.272 1040.177 105 0.764 106 0.307 107 0.912 108 0.193 109 0.312 110 0.320 1110.184 112 0.128 113 0.120 114 0.131 116 0.136 117 0.375 118 >10 (0%) 1190.554 120 0.328 122 0.238 123 0.264 126 0.185 127 0.214 130 0.250 1310.285 132 0.365 133 0.223 134 0.058 135 0.236 136 2.124 137 0.949 1383.188 139 2.962 140 0.152 141 >10 (8.8%) 142 0.055 143 0.045 144 0.051145 0.039 146 0.749 147 0.179 148 3.766 149 0.047 151 0.265 168 0.106172 0.270 182 0.230 183 0.414 184 0.182 185 0.189 186 0.074 204 0.023219 0.890 220 0.463 221 0.608 222 0.189 223 0.489 230 0.037 232 0.256233 0.120 236 0.070 238 0.036 240 0.035 241 0.183 242 0.042 243 0.094245 0.038 249 1.223 250 0.055 253 0.054 256 0.117 257 3.911 258 1.749261 0.101 265 0.106 266 0.057 268 0.104 271 0.114 273 0.083 275 0.012276 0.093 277 0.156 278 0.088 285 0.090 286 0.107 289 0.174 290 0.104291 0.710 292 0.375 293 2.268 294 0.161 296 >10 (14.6%) 301 0.101 3061.019 309 0.103 310 1.692 313 2.139 317 0.279 318 0.396 319 0.844 3253.564 326 1.722 328 0.113 329 0.162 330 >10 (15.0%) 331 >10 (28.7%) 3323.841 333 1.042 334 0.126 335 0.107 336 0.060 337 0.091 338 0.057 3390.699 340 0.346 359 0.013 373 6.427 374 0.211 375 >10 (44.7%) 376 0.113377 5.568 378 0.268 379 0.100 380 >10 (11.2%) 381 3.515 382 0.509 3830.116 384 0.162 385 0.211 386 0.106 387 >10 (46.4%) 388 0.139 389 0.561390 0.117 391 0.043 392 0.111 393 0.080 406 0.116 409 0.041 412 0.059419 0.069 420 0.449 422 0.107 423 0.040 427 3.676 428 0.138 429 0.073430 0.036 431 0.047 432 0.109 433 0.559 434 0.104 435 0.136 436 3.134437 0.500 438 2.511 439 0.048 440 >10 (48.0%) 441 0.228 442 0.116 4430.501 444 0.133 445 0.144 454 0.324 455 0.113 456 0.497 457 0.475 4580.214 459 0.055 461 0.043 462 0.193 463 0.159 464 0.480 465 0.231

Example 5

Representative compounds were screened using the assay procedure forDYRKIA kinase activity as described below.

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 μM to 0.00016 M) and compound transfer was performedusing the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-wellblack-walled round bottom plates (Corning).

The DYRKIA kinase assay was run using the Ser/Thr 18 peptide Z-lyteassay kit according to manufacturer's instructions (Life Technologies—aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as a ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant DYRKIA kinase, ATP and Ser/Thr peptide 18 wereprepared in 1× Kinase buffer to final concentrations of 0.19 μg/mL, 30μM, and 4 μM respectively. The mixture was allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 served as controlreactions. Additionally, an 11-point dose-response curve ofStaurosporine (1 uM top) was run to serve as a positive compoundcontrol.

After incubation, Development Reagent A was diluted in DevelopmentBuffer then added to the reaction and allowed to further incubate forone hour at room temperature. The plate was read at Ex 400 Em 455 todetect the coumarin signal and Ex 400 Em 520 to measure the signal(EnVision Multilabel Plate Reader, PerkinElmer).

The Emission ratio (Em) was calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation was then calculated using the followingformula: [1−((Em ratio×F₁₀₀%)−C₁₀₀%)/((C0%-C100%)+(Emratio×(F100%−F0%)))]. Dose-response curves were generated and inhibitoryconcentration (IC₅₀) values were calculated using non-linear regressioncurve fit in the Dotmatics' Studies Software (Bishops Stortford, UK).

Table 3 shows the measured activity for representative compounds ofFormula I as described herein.

TABLE 3 Compound EC₅₀ (μM) 1 0.0012 2 0.0013 3 0.0009 4 0.0025 5 0.00126 0.0011 7 0.0012 8 0.0009 9 0.0004 10 0.0010 11 0.0013 12 0.0029 130.0020 14 0.0009 15 0.3124 16 0.0011 17 0.0018 18 0.0017 19 0.0015 200.0552 21 0.0632 22 0.0551 23 0.0100 24 0.0673 25 0.1583 26 0.0412 270.0333 28 0.0011 29 0.0012 37 0.0009 40 0.0035 45 0.0018 47 0.0397 490.0042 52 0.0031 53 0.0020 54 0.0020 55 0.0011 56 0.0014 57 0.0026 590.0013 60 0.0037 61 0.0026 62 0.0023 63 0.0027 64 0.0033 65 0.0030 660.0055 67 0.0017 71 0.0019 72 0.0019 74 0.0070 76 0.0028 78 0.0021 800.0136 84 0.0029 85 0.0016 86 0.0019 87 0.0039 88 0.0028 89 0.0223 900.0023 91 0.0067 92 0.0010 93 0.0007 94 0.0013 95 0.0034 97 0.0013 990.0025 100 0.0444 101 0.0257 102 0.0093 103 0.0055 104 0.0077 105 0.0435106 0.0034 107 0.0021 108 0.0024 109 0.0022 110 0.0024 111 0.0017 1120.0023 113 0.0019 114 0.0022 116 0.0047 117 0.0056 118 0.0320 119 0.0103120 0.0127 122 0.0041 123 0.0035 126 0.0038 127 0.0053 130 0.0032 1314.9972 132 0.0032 133 0.0044 134 0.0016 135 0.0039 136 0.0038 137 0.0062138 0.0553 139 0.0185 140 0.0042 141 0.3745 142 0.0016 143 0.0015 1440.0012 145 0.0008 146 0.0374 147 0.0057 148 0.2215 149 0.0020 151 0.0043168 0.0034 172 0.0015 182 0.0063 183 0.0203 184 0.0311 185 0.0023 1860.0024 204 0.0021 219 0.0027 220 0.0063 221 0.0026 222 0.0014 223 0.0045230 0.0019 232 0.0017 233 0.0015 236 0.0012 238 0.0027 240 0.0018 2410.0025 242 0.0017 243 0.0024 245 0.0016 249 0.0018 250 0.0022 253 0.0014256 0.0017 257 0.0184 258 0.0189 261 0.0016 265 0.0019 266 0.0013 2680.0019 271 0.0021 273 0.0011 275 0.0006 276 0.0011 277 0.0008 278 0.0028285 0.0012 286 0.0008 289 0.0033 290 0.0029 291 0.0116 292 0.0057 2930.0145 294 0.0105 296 0.0053 301 0.0009 306 0.0023 309 0.0015 310 0.0017313 0.0021 317 0.0011 318 0.0017 319 0.0014 325 0.0018 326 0.0026 3280.0036 329 0.0046 330 0.0115 331 0.1220 332 0.3297 333 0.0435 334 0.0010335 0.0015 336 0.0011 337 0.0017 338 0.0010 339 0.0395 340 0.0012 3590.0037 373 0.0177 374 0.0038 375 0.0126 376 0.0067 377 0.0093 378 0.0028379 0.0025 380 0.8647 381 >10 (48.9%) 382 0.0023 383 0.0021 384 0.0012385 0.0009 386 0.0015 387 0.0030 388 0.0008 389 0.0053 390 0.0014 3910.0007 392 0.0011 393 0.0012 406 0.0027 409 0.0025 412 0.0022 419 0.0019420 0.0071 422 0.0026 423 0.0025 427 0.0137 428 0.0073 429 0.0064 4300.0023 431 0.0019 432 0.0016 433 0.0068 434 0.0013 435 0.0010 436 0.0212437 0.0013 438 0.0024 439 0.0024 440 0.0191 441 0.0011 442 0.0017 4430.0019 444 0.0021 445 0.0023 454 0.0059 455 0.0024 456 0.0030 457 0.0037458 0.0015 459 0.0014 461 0.0015 462 0.0017 463 0.0014 464 0.0058 4650.0087

Example 6

Representative compounds were screened using the assay procedure forGSK3β kinase activity as described below.

Each compound is dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:3, 11-point dose-responsecurves from 10 μM to 0.0003 μM) and compound transfer was performedusing the ECHO 550 (Labcyte, Sunnyvale, Calif.) into 1536-wellblack-walled round bottom plates (Corning).

The GSK3β kinase assay is run using the Ser/Thr 09 peptide Z-lyte assaykit according to manufacturer's instructions (Life Technologies-aDivision of Thermo-Fisher). This is a non-radioactive assay usingfluorescence resonance energy transfer (FRET) between coumarin andfluorescein to detect kinase activity which is represented as ratio ofcoumarin emission/fluorescein emission.

Briefly, recombinant GSK30 kinase, ATP and Ser/Thr peptide 09 areprepared in 1× Kinase buffer to final concentrations of 0.04 μg/mL, 46μM, and 4 μM respectively. The mixture is allowed to incubate with therepresentative compounds for one hour at room temperature. All reactionswere performed in duplicate. Unphosphorylated (“0% Control”) andphosphorylated (“100% control”) forms of Ser/Thr 18 serve as controlreactions.

After incubation, diluted Development Buffer is added to the reactionand allowed to further incubate for one hour at room temperature. Theplate is read at Ex 400 Em 455 to detect the coumarin signal and Ex 400Em 520 to measure the signal (EnVision Multilabel Plate Reader,PerkinElmer).

The Emission ratio (Em) is calculated as a ratio of the coumarin (C)emission signal (at 445 nm)/Fluorescein (F) emission signal (at 520 nm).The percent phosphorylation is then calculated using the followingformula: [1−((Em ratio×F100%)−C100%)/((C0%-C100%)+(Emratio×(F100%−F0%)))].

Dose-response curves are generated and inhibitory concentration (IC₅₀)values are calculated using non-linear regression curve fit in theDotmatics' Studies Software (Bishops Stortford, UK).

Table 4 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 4 Compound EC₅₀ (μM) 1 3.346 2 3.689 3 3.726 4 2.066 5 3.250 62.931 7 0.330 8 0.668 9 3.403 10 1.842 11 3.895 12 4.032 13 4.265 140.479 15 9.838 16 1.258 17 1.532 18 3.756 19 6.027 20 9.838 21 9.838 229.838 23 >10 24 >10 25 >10 26 >10 27 >10 28 0.537 29 0.818 37 3.51940 >10 45 1.884 47 >10 49 >10 52 4.322 53 0.859 54 2.421 55 1.435 563.967 57 2.037 59 3.856 60 0.439 61 2.225 62 2.825 63 2.701 64 5.842 651.085 66 2.712 67 3.649 71 0.728 72 5.046 74 4.124 76 0.937 78 1.29180 >10 84 1.523 85 0.506 86 3.051 87 3.566 88 8.925 89 7.389 90 3.862 919.164 92 5.321 93 6.272 94 4.553 95 >10 97 6.640 99 1.566 100 >10101 >10 102 9.067 103 0.040 104 0.012 105 0.009 106 0.002 107 0.010 1080.001 109 0.469 110 1.795 111 2.150 112 3.832 113 1.713 114 2.137 1161.138 117 >10 118 >10 119 >10 120 >10 122 4.616 123 0.492 126 2.097 1272.891 130 4.464 131 >10 (5.2%) 132 >10 133 3.207 134 >10 135 7.398136 >10 137 >10 138 0.666 139 >10 140 >10 141 >10 142 6.388 143 3.270144 1.359 145 3.694 146 >10 147 7.824 148 >10 149 2.941 151 >10 168 >10172 >10 182 1.882 183 0.704 184 1.959 185 1.445 186 1.859 204 0.763 2190.986 220 4.438 221 0.343 222 0.780 223 1.914 230 0.886 232 0.112 2330.100 236 0.299 238 0.750 240 0.212 241 0.514 242 0.361 243 0.809 2450.740 249 1.090 250 0.568 253 0.295 256 0.378 257 >10 258 >10 261 1.884265 3.429 266 2.498 268 3.128 271 4.550 273 2.901 275 4.177 276 1.853277 1.520 278 >10 285 0.256 286 0.938 289 6.000 290 >10 291 2.176 2921.876 293 3.571 294 6.573 296 >10 301 8.288 306 >10 309 2.693 310 0.584313 7.538 317 >10 318 2.822 319 7.099 325 5.953 326 6.980 328 1.410 3290.811 330 >10 331 >10 332 5.472 333 >10 334 0.593 335 0.685 336 1.477337 3.832 338 2.073 339 8.182 340 2.603 359 1.833 373 >10 374 5.461375 >10 376 >10 377 >10 378 3.696 379 3.192 380 >10 381 >10 (6.1%) 3820.367 383 0.829 384 0.212 385 0.256 386 0.608 387 0.101 388 0.085 3890.827 390 0.955 391 0.595 392 1.957 393 0.460 406 0.142 409 0.242 4120.368 419 1.164 420 0.333 422 1.201 423 0.351 427 >10 428 1.412 4291.658 430 0.610 431 0.563 432 4.216 433 7.370 434 1.860 435 2.368436 >10 437 3.472 438 1.646 439 0.453 440 4.544 441 4.314 442 7.115 4435.029 444 4.103 445 0.003 454 1.350 455 2.892 456 2.226 457 >10 4580.010 459 3.845 461 3.198 462 >10 (41.3%) 463 0.261 464 9.708 465 >10(51.0%)

Example 7

Representative compounds were screened using the assay procedure toassess the effect on cell viability as described below.

SW480 colon carcinoma cells were transduced with a lentiviral vectorexpressing luciferase with a human Sp5 promoter consisting of a sequenceof eight TCF/LEF binding sites. SW480 cells stably expressing theSp5-Luc reporter gene and a hygromycin resistance gene were selected bytreatment with 150 μg/mL of hygromycin for 7 days. These stablytransduced SW480 cells were expanded in cell culture and used for allfurther screening activities. Each compound was dissolved in DMSO as a10 mM stock and used to prepare compound source plates. Serial dilution(1:3, 8-point dose-response curves from 10 μM to 0.0045 μM) and compoundtransfer was performed using the ECHO 550 (Labcyte, Sunnyvale, Calif.)into 384-well white solid bottom assay plates (Greiner Bio-One) withappropriate DMSO backfill for a final DMSO concentration of 0.1%.

For the Cell Viability Assays, the cells were plated at 2,000 cells/wellin 384-well plates with a DMEM medium containing 1% fetal bovine serum,and 1% Penicillin-Streptomycin and incubated for four days hours at 37°C. and 5% CO₂. Eight replicates of DMSO-treated cells served as controlsand cells treated with compound were performed in duplicate.

After incubation, 10 μL of CellTiter-Glo (Promega) was added to eachwell allowed to incubate for approximately 12 minutes. This reagent“results in cell lysis and generation of a luminescent signalproportional to the amount of ATP present. The amount of ATP is directlyproportional to the number of cells present in culture, in agreementwith previous reports. The CellTiter-Glo® Assay generates a “glow-type”luminescent signal, produced by the luciferase reaction (Promega.com)”.

After incubation, the plates were read at Ex 560 nm Em 590 nm (Cytation3, BioTek). Dose-response curves were generated and EC₅₀ concentrationvalues were calculated using non-linear regression curve fit in theGraphPad Prism (San Diego, Calif.) or Dotmatics' Studies Software(Bishops Stortford, UK). For EC₅₀ of >10 μM, the percent inhibition at10 μM is provided.

Table 5 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 5 Compound EC₅₀ (μM) 1 0.165 2 0.091 3 0.105 4 0.390 5 0.038 60.049 7 0.089 8 0.087 9 0.037 10 0.101 11 0.222 12 0.632 13 0.159 140.269 15 >10 16 0.048 17 0.075 18 0.137 19 0.080 20 0.478 21 0.677 220.745 23 0.733 24 9.391 25 >10 26 1.700 27 >10 28 0.547 29 0.368 370.060 40 0.826 45 0.187 47 2.900 49 0.430 52 1.454 53 0.072 54 0.060 550.076 56 0.094 57 0.476 59 0.213 60 0.886 61 0.406 62 0.455 63 0.225 640.413 65 0.427 66 0.111 67 0.139 71 0.044 72 0.107 74 0.266 76 0.564 783.556 80 0.869 84 0.059 85 0.234 86 0.402 87 5.293 88 0.228 89 >10(41.5%) 90 0.165 91 0.415 92 0.323 93 0.126 94 0.470 95 7.608 97 0.18299 0.089 100 >10 (34.8%) 101 3.251 102 4.969 103 4.344 104 0.037 1050.694 106 0.367 107 0.890 108 0.567 109 0.834 110 0.675 111 0.447 1120.318 113 0.369 114 0.410 116 0.210 117 0.544 118 >10 (10.6%) 119 0.649120 0.058 122 0.301 123 0.400 126 0.105 127 0.149 130 0.360 131 0.406132 0.359 133 0.258 134 0.242 135 2.292 136 2.127 137 1.542 138 4.142139 4.949 140 0.308 141 >10 (12.2%) 142 0.099 143 0.114 144 0.100 1450.080 146 3.190 147 0.318 148 2.174 149 0.073 151 0.343 168 0.121 1720.486 182 0.464 183 0.586 184 0.325 185 0.236 186 0.115 204 0.058 2192.255 220 0.645 221 1.413 222 0.371 223 4.893 230 0.084 232 0.418 2330.310 236 0.193 238 0.065 240 0.066 241 0.446 242 2.437 243 0.214 2450.123 249 2.519 250 0.159 253 0.238 256 0.277 257 3.581 258 2.221 2610.286 265 0.174 266 0.174 268 0.168 271 0.460 273 0.106 275 0.012 2760.503 277 0.569 278 1.583 285 0.690 286 0.297 289 0.405 290 0.234 2912.771 292 0.491 293 3.024 294 0.469 296 >10 (17.3%) 301 0.682 306 2.492309 0.310 310 4.996 313 2.796 317 1.730 318 0.799 319 5.486 325 9.738326 2.651 328 0.334 329 0.512 330 >10 (13.3%) 331 6.588 332 5.109333 >10 (45.9%) 334 0.275 335 0.266 336 0.246 337 0.400 338 0.328 3394.763 340 1.050 359 0.045 373 6.837 374 0.383 375 >10 (23.5%) 376 0.387377 8.204 378 0.852 379 0.464 380 >10 (19.9%) 381 9.050 382 7.854 3830.276 384 0.426 385 4.465 386 0.222 387 >10 (32.4%) 388 0.334 389 0.595390 0.388 391 0.132 392 0.260 393 0.475 406 0.336 409 0.124 412 0.218419 0.273 420 0.542 422 3.151 423 0.113 427 8.055 428 0.403 429 0.464430 0.058 431 0.089 432 0.273 433 1.091 434 0.245 435 0.429 436 3.641437 0.782 438 3.528 439 0.108 440 4.307 441 0.535 442 0.283 443 1.052444 0.272 445 0.470 454 0.578 455 0.112 456 0.765 457 0.449 458 0.208462 0.443 463 0.381 464 0.481 465 0.413

Example 6

Representative compounds were screened using the assay procedure for tauphosphorylation activity described below.

SH-SY5Y cells (human neuroblastoma) were cultured in DMEM/F-12 mediumsupplemented with 15% FBS, Non-essential Amino Acid andPenicillin/Streptomycin. Two days before treatment, cells were seededonto 96 well plates at 5×10⁴ cells/well.

The above synthesized compounds were screened using the cell assayprocedure to assess decrease Tau phosphorylation at Ser396 (pSer396)described below.

DMSO-resuspended compounds were dispensed to 8 wells as a serialtitration from 10 μM to 4.6 nM final in medium and cells were exposedovernight (16-18 h) in a humidified incubator at 36.6c before harvest.Wells were visually checked for cell death or change in morphology andsupernatants were tested for cytotoxicity by measurement of lactatedehydrogenase release (LDH, CytoToxOne kit, Promega) if necessary. Ascontrols, commercially available DYRKIA inhibitors, Harmine and Indywhich were shown to have good DYRK1A inhibition in the kinase assay withno CDK1 activity (EC₅₀ 18 and 53 nM respectively, 6 μM for CDK1) butweak EC₅₀ in the Tau assay >10 μM.

Cells were lysed with RIPA buffer complemented with phosphatase andprotease inhibitors then lysates were spun down at 12,000 g for 10 minto remove any cellular debris. Lysates are then either directly testedfor pSer396 by ELISA (Life Technology, Kit KHB7031) or loaded on NuPageBis-Tris gels for western blot analysis. Colorimetric detection of ELISAsignal is performed by Cytation3 plate reader (Biotek) and thechemiluminescence signal for HRP-linked antibodies used in westernblotting is detected using a Carestream Image Station. The same pSer396antibody is used for detection of pTau in both assays.

Blot densitometry for pSer396 and β-actin were analyzed using ImageJ(NIH) and pSer396 Tau ELISA signal was used to plot, draw the curvefitting, and determine each compounds EC₅₀ in Prism (GraphPad).

Table 6 shows the activity of representative compounds as providedherein.

TABLE 6 pSer396 Tau EC₅₀ Compound (μM) 5 1.390 6 >10 7 1.100 14 3.900 603.500 109 >10 221 >10 232 0.095 233 0.174 236 >10 240 >10 242 >10 2531.800 256 1.200 285 7.600 382 >10 384 0.583 385 0.337 387 >10 388 1.100393 >10 406 >10 409 >10 412 >10 420 >10 423 5.600

Example 7

Representative compounds were screened using primary human fibroblasts(derived from IPF patients) treated with TGF-β1 to determine theirability to inhibit the fibrotic process.

Human Fibroblast Cell Culture:

Primary human fibroblasts derived from IPF patients (LL29 cells)[¹Xiaoqiu Liu, et. al., “Fibrotic Lung Fibroblasts Show BluntedInhibition by cAMP Due to Deficient cAMP Response Element-BindingProtein Phosphorylation”, Journal of Pharmacology and ExperimentalTherapeutics (2005), 315(2), 678-687; ²Watts, K. L., et. al., “RhoAsignaling modulates cyclin D1 expression in human lung fibroblasts;implications for idiopathic pulmonary fibrosis”, Respiratory Research(2006), 7(1), 88] were obtained from American Type Culture Collection(ATCC) and expanded in F₁₂ medium supplemented with 15% Fetal BovineSerum and 1% Penicillin/Streptomycin.

Compound Screening:

Each compound was dissolved in DMSO as a 10 mM stock and used to preparecompound source plates. Serial dilution (1:2, 11-point dose-responsecurves from 10 μM to 0.94 nM) and compound transfer was performed usingthe ECHO 550 (Labcyte, Sunnyvale, Calif.) into 384-well clear bottomassay plates (Greiner Bio-One) with appropriate DMSO backfill for afinal DMSO concentration of 0.1%. LL29 cells were plated at 1,500cells/well in 70 μL/well F₁₂ medium supplemented with 1% Fetal BovineSerum. TGF-β1 (Peprotech; 20 ng/mL) was added to the plates to inducefibrosis (ref. 1 and 2 above). Wells treated with TGF-β1 and containingDMSO were used as positive control, and cells with only DMSO werenegative control. Cells were incubated at 37° C. and 5% CO₂ for 4 days.Following incubation for 4 days, SYTOX green nucleic acid stain (LifeTechnologies [Thermo Fisher Scientific]) was added to the wells at afinal concentration of 1 μM and incubated at room temperature for 30min. Cells were then fixed using 4% formaldehyde (Electron MicroscopySciences), washed 3 times with PBS followed by blocking andpermeabilization using 3% Bovine Serum Albumin (BSA; Sigma) and 0.3%Triton X-100 (Sigma) in PBS. Cells were then stained with antibodyspecific to α-smooth muscle actin (αSMA; Abcam) (ref. 1 and 2 above) in3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100 (Sigma) inPBS, and incubated overnight at 4° C. Cells were then washed 3 timeswith PBS, followed by incubation with Alexa Flor-647 conjugatedsecondary antibody (Life Technologies [Thermo Fisher Scientific]) andDAPI in 3% Bovine Serum Albumin (BSA; Sigma) and 0.3% Triton X-100(Sigma) in PBS at room temperature for 1 hour. Cells were then washed 3times with PBS and plates were sealed for imaging. αSMA staining wasimaged by excitation at 630 nm and emission at 665 nm and quantifiedusing the Compartmental Analysis program on the CellInsight CX5 (ThermoScientific). Dead or apoptotic cells were excluded from analysis basedon positive SYTOX green staining. % of total cells positive for αSMAwere counted in each well and normalized to the average of 11 wellstreated with TGF-β1 on the same plate using Dotmatics' Studies Software.The normalized averages (fold change over untreated) of 3 replicatewells for each compound concentration were used to create dose-responsescurves and EC₅₀ values were calculated using non-linear regression curvefit in the Dotmatics' Studies Software. For EC₅₀ of >10 μM, the percentinhibition at 10 μM is provided.

Table 7 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 7 Compound EC₅₀ (μM) 1 0.079 2 1.162 3 0.158 4 0.239 5 0.179 60.195 7 2.563 8 0.196 9 0.083 10 0.085 11 0.071 12 1.058 13 0.194 140.061 15 >10 (36.3%) 16 1.000 17 0.937 18 0.152 19 0.083 20 3.881 212.370 22 3.826 23 0.769 24 >10 (24.3%) 25 1.656 26 1.200 27 1.677 280.207 29 0.302 37 0.142 40 2.006 45 0.992 47 1.099 49 1.249 52 3.894 530.553 54 0.120 55 0.081 56 >10 (30.2%) 57 0.133 59 0.013 60 >10 (24.6%)61 0.694 62 0.167 63 0.263 64 >10 (40.9%) 65 1.991 66 0.603 67 0.030 711.915 72 0.135 74 6.836 78 >10 (0.5%) 84 0.094 85 1.244 86 0.433 87 >10(48.7%) 91 0.204 92 0.708 93 0.270 94 0.678 95 >10 (3.0%) 97 0.117 990.079 100 0.829 101 5.193 102 0.820 109 0.601 110 0.187 111 0.167 1120.181 113 0.217 114 0.186 116 0.298 122 1.296 123 0.262 127 0.207 1300.273 131 0.154 132 >10 (37.6%) 133 0.151 134 0.244 135 0.653 136 0.312137 0.333 138 1.525 139 2.120 140 0.317 143 0.094 145 0.092 146 1.847147 0.128 148 1.251 149 0.149 151 0.859 168 0.466 172 0.463 182 0.509183 0.644 184 0.194 185 0.300 186 0.585 204 0.143 219 >10 (25.1%) 2200.276 221 0.978 222 0.190 223 >10 (13.5%) 230 0.181 232 0.612 233 0.144236 >10 (39.7%) 238 0.145 240 0.120 241 0.499 242 0.197 245 2.152 2493.022 250 0.127 253 0.360 256 0.752 257 1.202 258 0.329 261 1.246 2650.293 266 0.353 268 0.324 271 0.133 273 0.253 275 0.292 276 0.147 2770.869 278 5.494 285 1.391 286 0.665 289 0.329 290 0.562 291 6.396 2921.264 293 5.338 294 0.544 296 0.198 301 0.501 306 0.820 309 0.392 3100.920 313 0.306 317 1.139 318 1.480 319 4.728 325 0.863 326 0.611 3280.159 329 0.339 330 >10 (6.0%) 331 2.196 332 2.230 333 >10 (15.8%) 3340.090 335 0.196 336 0.254 337 1.589 338 0.335 339 3.846 340 0.299 3590.087 373 1.270 374 1.382 375 2.654 376 1.043 377 2.701 378 1.292 3790.379 380 4.899 381 >10 (38.4%) 382 0.624 383 0.438 384 0.406 385 1.948386 0.437 387 >10 (37.7%) 388 0.807 389 4.200 390 0.538 391 2.764 3920.297 393 0.350 406 1.280 409 0.281 412 0.245 419 1.005 420 2.467 4220.202 423 0.307 427 4.578 428 >10 (12.5%) 429 0.411 430 0.139

Example 8

Representative compounds were screened using the following assayprocedure to determine their ability to inhibit IL-6 and thereforedemonstrate their anti-inflammatory properties.

Human Peripheral Blood Mononuclear Cells:

Fresh Normal PB MNC (Catalog #PB001, AllCells, Alameda, Calif.) wereshipped overnight at 4° C. and resuspended in Roswell Park MemorialInstitute (RPMI) 1640 Medium, with GlutaMAX Supplement (Catalog#61870127, ThermoFisher Scientific, Waltham, Mass.) supplemented with 1%Penicillin-Streptomycin (Catalog #15140163, ThermoFisher Scientific,Waltham, Mass.) and 1% fetal bovine serum (FBS) (Catalog #16140089,ThermoFisher Scientific, Waltham, Mass.) assay media.

Compound Screening:

Fresh normal human peripheral blood mononuclear cells (huPBMCs) wereresuspended in 1% FBS-RPMI assay media with 1% Penicillin-Streptomycin1% to a cell concentration of 1×10e6 cells/mL. Each compound wasdissolved in DMSO (Catalog #D8418-100 ml, Sigma-Aldrich, St. Louis, Mo.)as a 10 mM stock and used to prepare compound source plates. Serialdilution (1:3, 10-point dose-response curves starting from 10 M) andcompound transfer was performed using the ECHO 550 (Labcyte, Sunnyvale,Calif.) into 384-well white Proxiplate-Plus assay plates (Catalog#6008289, PerkinElmer, Shelton, Conn.) with appropriate DMSO backfillfor a final DMSO concentration of 0.25%. huPBMCs were plated at 5000cells/well in the 384-well Proxiplate-Plus assay plates and incubated at37° C.-5% CO₂ for 2 hours. 50 ng/mL of Lipopolysaccharides fromEscherichia coli 0111:B4 (Catalog #L5293-2ML, Sigma-Aldrich, St. Louis,Mo.) was added after 2 hours and cells were incubated for another 22hours at 37° C.-5% CO₂. After 22 hour incubation, a mixture of anti-IL6XL665 and anti-IL-6 Cryptate diluted in reconstitution buffer (Catalog#62IL6PEC, Cisbio Inc., Bedford, Mass.) was added to each well.Following incubation for 3 hours at room temperature, HomogeneousTime-Resolved Fluorescence (HTRF) was measured using the Envision(Perkin Elmer, Shelton, Conn.) at 665 nm and 620 nM. The ratio offluorescence at 665 nm to 620 nm was used as a readout for IL-6quantification. All samples were processed in duplicate. Readings werenormalized to DMSO treated cells and normalized activities were utilizedfor EC₅₀ calculations. EC₅₀ was determined using software generated byDotmatics Limited (Windhill Bishops Stortford Herts, UK) using theLevenberg-Marquardt 4 parameter fitting procedure with finite differentgradients. For EC₅₀ of >10 μM, the percent inhibition at 10 μM isprovided.

Table 8 shows the activity of representative compounds of Formula I asprovided herein.

TABLE 8 Compound EC₅₀ (μM) 1 0.389 2 0.270 3 0.287 4 1.714 5 0.143 60.173 7 0.307 8 1.541 9 0.166 10 0.428 11 0.215 12 2.621 13 0.489 140.584 15 >10 (2.8%) 16 0.805 17 1.028 18 0.376 19 0.194 20 1.178 211.323 22 1.209 23 2.474 24 >10 (5.5%) 25 >10 (41.8%) 26 4.477 27 4.51028 0.834 29 0.669 37 0.379 40 3.648 45 1.499 47 1.301 49 0.614 52 >10(31.2%) 53 1.156 54 0.208 55 0.308 56 0.172 57 0.364 59 0.339 60 >10(9.6%) 61 2.625 62 0.725 63 0.455 64 1.329 65 2.815 66 0.259 67 0.293 710.477 72 0.196 74 0.485 76 3.190 78 >10 (6.0%) 80 >10 (31.3%) 84 0.18785 1.049 86 >10 (36.2%) 87 >10 (13.4%) 88 1.562 89 >10 (4.0%) 90 1.08191 1.858 92 0.671 93 1.811 94 2.007 95 1.653 97 0.823 99 0.791 100 >10(1.3%) 101 >10 (18.2%) 102 >10 (12.2%) 103 1.081 104 1.125 105 0.362 1060.369 107 0.426 108 0.361 109 1.699 110 0.942 111 1.048 112 4.463 1130.791 114 1.386 116 2.346 117 3.252 118 >10 (14.3%) 119 >10 (17.4%) 1201.383 122 >10 (41.7%) 123 1.187 126 >10 (6.0%) 127 >10 (26.1%) 130 >10(18.3%) 131 >10 (16.4%) 132 >10 (8.3%) 133 >10 (35.2%) 134 >10 (46.7%)135 7.724 136 2.355 137 3.928 138 >10 (4.5%) 139 >10 (1.2%) 140 3.093141 >10 (4.6%) 142 0.666 143 0.232 144 0.375 145 0.293 146 >10 (22.4%)147 0.650 148 >10 (5.2%) 149 0.307 151 1.042 168 1.161 172 0.890 1820.613 183 0.733 184 4.005 185 0.865 186 0.216 204 2.637 219 7.679 2203.292 221 3.773 222 1.486 223 >10 (12.7%) 230 0.216 232 7.768 233 0.566236 2.136 238 0.325 240 0.237 241 1.118 242 0.349 243 2.657 245 1.211249 3.976 250 1.503 253 1.274 256 0.744 257 >10 (3.9%) 258 >10 (12.9%)261 2.599 265 0.936 266 0.371 268 2.838 271 1.610 273 0.829 275 0.292276 3.078 277 0.819 278 3.352 285 3.009 286 1.123 289 0.828 290 1.410291 >10 (47.1%) 292 9.705 293 >10 (32.2%) 294 >10 (48.9%) 296 >10 (4.4%)301 >10 (33.0%) 306 3.107 309 5.244 310 >10 (17.3%) 313 8.611 317 >10(11.4%) 318 5.272 319 >10 (3.7%) 325 >10 (9.7%) 326 8.423 328 9.285 3293.206 330 >10 (6.8%) 331 5.799 332 7.290 333 >10 (18.2%) 334 3.891 3353.535 336 1.579 337 >10 (4.0%) 338 3.821 339 >10 (6.3%) 340 2.114 3593.396 373 >10 (8.0%) 374 >10 (12.1%) 375 >10 (4.3%) 376 >10 (11.9%)377 >10 (4.8%) 378 >10 (27.0%) 379 1.594 380 >10 (3.1%) 381 >10 (26.4%)382 >10 (11.8%) 383 1.048 384 1.060 385 >10 (23.4%) 386 5.074 387 >10(6.1%) 388 1.140 389 >10 (27.6%) 390 7.186 391 0.867 392 8.722 393 1.119406 >10 (15.1%) 409 >10 (32.5%) 412 1.180 419 >10 (43.6%) 420 >10(11.7%) 422 0.452 423 4.204 427 >10 (15.6%) 428 >10 (36.4%) 429 1.806430 0.388 431 0.499 432 1.157 433 >10 (12.5%) 434 3.259 435 >10 (7.2%)436 >10 (11.3%) 437 2.718 438 >10 (30.9%) 439 0.747 440 >10 (4.7%) 4410.819 442 1.286 443 >10 (47.2%) 444 0.921 445 0.992 454 1.217 455 0.749456 2.203 457 1.852 458 0.170

What is claimed is:
 1. A method of treating a fibrotic disorder in apatient, wherein the fibrotic disorder is selected from: skin fibrosis,scleroderma, lung fibrosis, muscle fibrosis, kidney fibrosis, uterinefibrosis, renal fibrosis, liver fibrosis, and pulmonary fibrosis, themethod comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof:

wherein: R¹, R², R⁴, and R⁵ are independently selected from the groupconsisting of H, halide, amino, unsubstituted —(C₁₋₃ haloalkyl), andunsubstituted —(C₁₋₃ alkyl); R³ is selected from the group consistingof:

wherein each of R⁷-R³⁵ is, independently, a substituent as definedanywhere herein or a single bond connecting R³ to the isoquinoline ring;wherein only one of R⁷-R¹⁰ (when present) is a bond, only one of R¹¹-R¹⁴(when present) is a bond, only one of R¹⁵-R¹⁷ (when present) is a bond,only one of R¹⁸-R²⁰ (when present) is a bond, only one of R²¹-R²³ (whenpresent) is a bond, only one of R²⁴-R²⁶ (when present) is a bond, onlyone of R²⁷-R²⁹ (when present) is a bond, only one of R³⁰-R³¹ (whenpresent) is a bond, only one of R³²-R³³ (when present) is a bond, andonly one of R³⁴-R³⁵ (when present) is a bond; wherein any one of thenitrogen atoms attached to R⁷, R¹¹, R¹⁵, R¹⁸, or R²¹ can serve as thepoint of attachment of R³ to the isoquinoline ring; wherein any one ofthe carbon atoms attached to R⁸, R⁹, R¹⁰, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁹,R²⁰, R²³, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³¹, R³², R³³, R³⁴, orR³⁵ can serve as the point of attachment of R³ to the isoquinoline ring;as that: when the nitrogen atom to which R⁷ is attached serves as thepoint of attachment of R³ to the isoquinoline ring, then R⁷ is a singlebond connecting R³ to the isoquinoline ring; when the carbon atom towhich R⁸ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R⁸ is a single bond connecting R³ to theisoquinoline ring; when the carbon atom to which R⁹ is attached servesas the point of attachment of R³ to the isoquinoline ring, then R⁹ is asingle bond connecting R³ to the isoquinoline ring; when the carbon atomto which R¹⁰ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁰ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹¹ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹¹ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹² is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹² is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R¹³ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹³ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁴ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁴ is a single bond connecting R³to the isoquinoline ring; when the nitrogen atom to which R¹⁵ isattached serves as the point of attachment of R³ to the isoquinolinering, then R¹⁵ is a single bond connecting R³ to the isoquinoline ring;when the carbon atom to which R¹⁶ is attached serves as the point ofattachment of R³ to the isoquinoline ring, then R¹⁶ is a single bondconnecting R³ to the isoquinoline ring; when the carbon atom to whichR¹⁷ is attached serves as the point of attachment of R³ to theisoquinoline ring, then R¹⁷ is a single bond connecting R³ to theisoquinoline ring; when the nitrogen atom to which R¹⁸ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR¹⁸ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R¹⁹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R¹⁹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁰ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁰ is a single bond connecting R³ to the isoquinoline ring; when thenitrogen atom to which R²¹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²¹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²² is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²² is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²³ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²³ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁴ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁴ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁵ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁵ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁶ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁶ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁷ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁷ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R²⁸ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR²⁸ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R²⁹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R²⁹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³⁰ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³⁰ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³¹ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³¹ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³² is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³² is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³³ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³³ is a single bond connecting R³to the isoquinoline ring; when the carbon atom to which R³⁴ is attachedserves as the point of attachment of R³ to the isoquinoline ring, thenR³⁴ is a single bond connecting R³ to the isoquinoline ring; when thecarbon atom to which R³⁵ is attached serves as the point of attachmentof R³ to the isoquinoline ring, then R³⁵ is a single bond connecting R³to the isoquinoline ring; R⁶ is selected from the group consisting of-phenyl substituted with 1-5 R³⁶, —(C₁₋₃ alkylene)_(p)pyridinyloptionally substituted with 1-6 R³⁷, and a 6-10 membered heteroaryloptionally substituted with 1-6 R³⁷; wherein the carbonyl of Formula Iis attached to an aromatic ring of the heteroaryl; wherein —(C₁₋₃alkylene) is optionally substituted with one or more substituents asdefined anywhere herein; R⁷ is selected from the group consisting of asingle bond, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein —(C₁₋₄alkylene) is optionally substituted with one or more substituents asdefined anywhere herein; R⁸, R⁹, and R¹⁰ are independently selected fromthe group consisting of a single bond, H, halide, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; alternatively, one of R⁷ and R⁸, R⁸ and R⁹, orR⁹ and R¹⁰ are taken together to form a ring which is selected from thegroup consisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰and -carbocyclyl optionally substituted with 1-12 R⁴¹; R¹¹ is selectedfrom the group consisting of a single bond, H, unsubstituted —(C₁₋₉alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;R¹², R¹³, and R¹⁴ are independently selected from the group consistingof a single bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; alternatively,one of R¹¹ and R¹², R¹² and R¹³, or R¹⁴ and R¹¹ are taken together toform a ring which is selected from the group consisting of -heterocyclyloptionally substituted with 1-10 R⁴⁰ and -carbocyclyl optionallysubstituted with 1-12 R⁴¹; R¹⁵ is selected from the group consisting ofa single bond, H, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein —(C₁₋₄ alkylene) is optionally substituted with one or moresubstituents as defined anywhere herein; R¹⁶ and R¹⁷ are independentlyselected from the group consisting of a single bond, H, halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; alternatively, one of R¹⁵ andR¹⁶ or R¹⁶ and R¹⁷ are taken together to form a ring which is selectedfrom the group consisting of -heterocyclyl optionally substituted with1-10 R⁴⁰ and -carbocyclyl optionally substituted with 1-12 R⁴¹; R¹⁸ isselected from the group consisting of a single bond, H, unsubstituted—(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂,—(C₁₋₄ alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;R¹⁹ and R²⁰ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; alternatively,one of R¹⁸ and R¹⁹ or R¹⁸ and R²⁰ are taken together to form aheterocyclyl optionally substituted with 1-10 R⁴⁰; R²¹ is selected fromthe group consisting of a single bond, H, unsubstituted —(C₁₋₉ alkyl),unsubstituted —(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl),unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄ alkylene)N(R⁴⁸)₂, —(C₁₋₄alkylene)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyloptionally substituted with 1-10 R³⁸, and -carbocyclyl optionallysubstituted with 1-12 R³⁹; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;R²² and R²³ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; alternatively,R²² and R²³ are taken together to form a ring which is selected from thegroup consisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰and -carbocyclyl optionally substituted with 1-12 R⁴¹; R²⁴, R²⁵, and R²⁶are independently selected from the group consisting of a single bond,H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; alternatively, one of R²⁴ andR²⁵ or R²⁵ and R²⁶ are taken together to form a ring which is selectedfrom the group consisting of -heterocyclyl optionally substituted with1-10 R⁴⁰ and -carbocyclyl optionally substituted with 1-12 R⁴¹; R²⁷,R²⁸, and R²⁹ are independently selected from the group consisting of asingle bond, H, halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted—(C₂₋₉ alkenyl), unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉haloalkyl), —(C₁₋₄ alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹,—C(═O)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substitutedwith 1-10 R³⁸, and -carbocyclyl optionally substituted with 1-12 R³⁹;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; alternatively,R²⁷ and R²⁸ are taken together to form a ring which is selected from thegroup consisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰and -carbocyclyl optionally substituted with 1-12 R⁴¹; R³⁰ and R³¹ areindependently selected from the group consisting of a single bond, H,halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; alternatively, R³⁰ and R³¹ aretaken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰ and-carbocyclyl optionally substituted with 1-12 R⁴¹; R³² and R³³ areindependently selected from the group consisting of a single bond, H,halide, unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; R³⁴ and R³⁵ are independentlyselected from the group consisting of a single bond, H, halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —(C₁₋₄alkylene)_(p)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)OR⁴⁹, —C(═O)N(R⁴⁸)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R³⁸, and-carbocyclyl optionally substituted with 1-12 R³⁹; wherein each —(C₁₋₄alkylene) is, independently, optionally substituted with one or moresubstituents as defined anywhere herein; alternatively, R³⁴ and R³⁵ aretaken together to form a ring which is selected from the groupconsisting of -heterocyclyl optionally substituted with 1-10 R⁴⁰ and-carbocyclyl optionally substituted with 1-12 R⁴¹; each R³⁶ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁷ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₉ alkyl), unsubstituted —(C₂₋₉ alkenyl),unsubstituted —(C₂₋₉ alkynyl), unsubstituted —(C₁₋₉ haloalkyl), —XR⁴²,—C(═O)N(R⁴⁷)₂, —(C₁₋₄ alkylene)_(p)N(R⁵⁰)₂, —(C₁₋₄alkylene)_(p)heterocyclyl optionally substituted with 1-10 R⁴³, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁸ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R³⁹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴⁰ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN, and—(C₁₋₄ alkylene)_(p)carbocyclyl optionally substituted with 1-12 R⁴⁴;wherein each —(C₁₋₄ alkylene) is, independently, optionally substitutedwith one or more substituents as defined anywhere herein; each R⁴¹ isindependently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴² is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —(C₁₋₄alkylene)N(R⁴⁸)₂, —(C₁₋₄ alkylene)_(p)aryl optionally substituted with1-10 R⁴⁶, —(C₁₋₄ alkylene)_(p)heterocyclyl optionally substituted with1-12 R⁴³, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionally substitutedwith 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is, independently,optionally substituted with one or more substituents as defined anywhereherein; each R⁴³ is independently selected from the group consisting ofhalide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), —CN,—OH, —C(═O)R⁵¹, —N(R⁵⁰)₂, and —(C₁₋₄ alkylene)_(p)carbocyclyl optionallysubstituted with 1-12 R⁴⁴; wherein each —(C₁₋₄ alkylene) is,independently, optionally substituted with one or more substituents asdefined anywhere herein; each R⁴⁴ is selected from the group consistingof halide, unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴⁶ is independently selected from the group consisting of halide,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and —CN;each R⁴⁷ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted —(C₁₋₅ haloalkyl); eachR⁴⁸ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted -(C₁₋₅ haloalkyl); eachR⁴⁹ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), and unsubstituted -(C₁₋₅ haloalkyl); eachR⁵⁰ is independently selected from the group consisting of H,unsubstituted —(C₁₋₅ alkyl), unsubstituted —(C₂₋₅ alkenyl),unsubstituted —(C₂₋₅ alkynyl), unsubstituted —(C₁₋₅ haloalkyl), and—(C₁₋₄ alkylene)N(R⁴⁸)₂; wherein —(C₁₋₄ alkylene) is optionallysubstituted with one or more substituents as defined anywhere herein;each R⁵¹ is a heteroaryl optionally substituted with 1-6 R⁵²; each R⁵²is a -heterocyclyl optionally substituted with 1-10 R⁴⁶; each X isselected from the group consisting of O, S, and NR⁴⁸; each Y is selectedfrom the group consisting of O and S; and each p is independently 0or
 1. 2. The method of claim 1, wherein R¹, R², R⁴, and R⁵ are H.
 3. Themethod of claim 2, wherein R³ is selected from the group consisting of:


4. The method of claim 3, wherein R³ is selected from the groupconsisting of:

wherein R⁷, R¹¹, R¹⁴, R¹⁵, R¹⁸, and R¹⁹ are independently selected fromthe group consisting of H and —(C₁₋₃ alkyl).
 5. The method of claim 4,wherein R³ is

wherein R⁷ is —(C₁₋₃ alkyl).
 6. The method of claim 1 wherein R⁶ is-phenyl substituted with 1-5 R³⁶.
 7. The method of claim 4 wherein R⁶ is-phenyl substituted with 1-5 R³⁶.
 8. The method of claim 5, wherein R⁶is -phenyl substituted with 1-5 R³⁶.
 9. The method of claim 6, whereinR⁶ is -phenyl substituted with one R³⁶.
 10. The method of claim 7,wherein R⁶ is -phenyl substituted with one R³⁶.
 11. The method of claim8, wherein R⁶ is -phenyl substituted with one R³⁶.
 12. The method ofclaim 9, wherein R³⁶ is selected from the group consisting of halide,-heterocyclyl optionally substituted with 1-2 R⁴³, -CH₂heterocyclyloptionally substituted with 1-2 R⁴³, -Oheterocyclyl optionallysubstituted with 1-2 R⁴³, —NHheterocyclyl optionally substituted with1-2 R⁴³, —O(C₁₋₄ alkyl), and —O(C₁₋₄ haloalkyl).
 13. The method of claim10, wherein R³⁶ is selected from the group consisting of halide,-heterocyclyl optionally substituted with 1-2 R⁴³, -CH₂heterocyclyloptionally substituted with 1-2 R⁴³, -Oheterocyclyl optionallysubstituted with 1-2 R⁴³, —NHheterocyclyl optionally substituted with1-2 R⁴³, —O(C₁₋₄ alkyl), and —O(C₁₋₄ haloalkyl).
 14. The method of claim11, wherein R³⁶ is selected from the group consisting of halide,-heterocyclyl optionally substituted with 1-2 R⁴³, -CH₂heterocyclyloptionally substituted with 1-2 R⁴³, -Oheterocyclyl optionallysubstituted with 1-2 R⁴³, —NHheterocyclyl optionally substituted with1-2 R⁴³, —O(C₁₋₄ alkyl), and —O(C₁₋₄ haloalkyl).
 15. The method of claim1, wherein R⁶ is a 6-membered heteroaryl optionally substituted with 1-6R³⁷.
 16. The method of claim 4, wherein R⁶ is a 6-membered heteroaryloptionally substituted with 1-6 R³⁷.
 17. The method of claim 5, whereinR⁶ is a 6-membered heteroaryl optionally substituted with 1-6R³⁷. 18.The method of claim 15, wherein R⁶ is -pyridin-3-yl optionallysubstituted with one R³⁷.
 19. The method of claim 16, wherein R⁶ is-pyridin-3-yl optionally substituted with one R³⁷.
 20. The method ofclaim 17, wherein R⁶ is -pyridin-3-yl optionally substituted with oneR³⁷.
 21. The method of claim 15, wherein R⁶ is -pyridin-4-yl optionallysubstituted with one R³⁷.
 22. The method of claim 16, wherein R⁶ is-pyridin-4-yl optionally substituted with one R³⁷.
 23. The method ofclaim 17, wherein R⁶ is -pyridin-4-yl optionally substituted with oneR³⁷.
 24. The method of claim 21, wherein R³⁷ is selected from the groupconsisting of halide, —(C₁₋₃ alkyl), -heterocyclyl optionallysubstituted with 1-2 R⁴³, —CH₂heterocyclyl optionally substituted with1-2 R⁴³, -Oheterocyclyl optionally substituted with 1-2 R⁴³,—NHheterocyclyl optionally substituted with 1-2 R⁴³, —O(C₁₋₄ alkyl), and—O(C₁₋₄ haloalkyl).
 25. The method of claim 22, wherein R³⁷ is selectedfrom the group consisting of halide, —(C₁₋₃ alkyl), -heterocyclyloptionally substituted with 1-2 R⁴³, —CH₂heterocyclyl optionallysubstituted with 1-2 R⁴³, -Oheterocyclyl optionally substituted with 1-2R⁴³, —NHheterocyclyl optionally substituted with 1-2 R⁴³, —O(C₁₋₄alkyl), and —O(C₁₋₄ haloalkyl).
 26. The method of claim 23, wherein R³⁷is selected from the group consisting of halide, —(C₁₋₃ alkyl),-heterocyclyl optionally substituted with 1-2 R⁴³, —CH₂heterocyclyloptionally substituted with 1-2 R⁴³, -Oheterocyclyl optionallysubstituted with 1-2 R⁴³, —NHheterocyclyl optionally substituted with1-2 R⁴³, —O(C₁₋₄ alkyl), and —O(C₁₋₄ haloalkyl).
 27. The method of claim24, wherein R⁴³ is selected from the group consisting of unsubstituted—(C₁₋₃ alkyl), unsubstituted —(C₁₋₃ haloalkyl), and -carbocyclyloptionally substituted with 1-12 R⁴⁴.
 28. The method of claim 25,wherein R⁴³ is selected from the group consisting of unsubstituted—(C₁₋₃ alkyl), unsubstituted —(C₁₋₃ haloalkyl), and -carbocyclyloptionally substituted with 1-12 R⁴⁴.
 29. The method of claim 26,wherein R⁴³ is selected from the group consisting of unsubstituted—(C₁₋₃ alkyl), unsubstituted —(C₁₋₃ haloalkyl), and -carbocyclyloptionally substituted with 1-12 R⁴⁴.
 30. The method of claim 1, whereinthe compound of Formula I is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 31. The method of claim1, wherein the compound of Formula I is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 32. The method of claim1, wherein the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 33. The method of claim1, wherein the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 34. The method of claim1, wherein the compound of Formula I is selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 35. The method of claim1, wherein the fibrotic disorder is skin fibrosis.
 36. The method ofclaim 1, wherein the fibrotic disorder is scleroderma.
 37. The method ofclaim 1, wherein the fibrotic disorder is pulmonary fibrosis.
 38. Themethod of claim 1, wherein the fibrotic disorder is muscle fibrosis. 39.The method of claim 1, wherein the fibrotic disorder is kidney fibrosis.40. The method of claim 1, wherein the fibrotic disorder is liverfibrosis.